mechano biology
TRANSCRIPT
-
7/29/2019 Mechano Biology
1/14
1
REVIEW ARTICLE^ ^
Mechanobiology and diseases of
mechanotransductionDonald E Ingber
The current focus of medicine on molecular genetics ignoresThe current focus of medicine on molecular genetics ignores
Introduction
the physical basis of disease even though many of thethe physical basis of disease even though many of the The molecular biology revolution has led to advances
problems that lead to pain and morbidity, and bring patientsproblems that lead to pain and morbidity, and bring patients in knowledge and new technologies that are revolu-to the doctor'
s ofce, result from changes in tissue structureto the doctor's ofce, result from changes in tissue structure tionizing the way in which clinical medicine is
or mechanics. The main goal of this article is therefore toor mechanics. The main goal of this article is therefore to practiced. Completion of the Human Genome Pro-help integrate mechanics into our understanding of
the
help integrate mechanics into our understanding of the ject,massively parallel gene and protein prolingmolecular basis of disease. This article rst reviews the
keymolecular basis of disease. This article rst reviews the key techniques,and powerful bioinformatics tools are justroles that physical forces, extracellular matrix and cellr
oles that physical forces, extracellular matrix and cell a few examples. Yet there is a huge disconnectstructure play in the control of normal development, as w
ellstructure play in the control of normal development, as well between these genome-age' technologies and theas in the maintenance of tissue form and function. Rece
ntas in the maintenance of tissue form and function. Recent reality of how diseases manifest themselves. Frominsights into cellular mechanotransduction the mo
lecularinsights into cellular mechanotransduction the molecular the time the rst human looked,listened and felt formechanism by which cells sense and respond to mechani
calmechanism by which cells sense and respond to mechanical what is wrong with a sick friend,caregivers havestress also are described. Re-evaluation of hum
anstress also are described. Re-evaluation of human recognized the undeniable physical basis of disease.pathophysiology in this context reveals that a wide ra
ngepathophysiology in this context reveals that a wide range The thrill in the chest of a patient with aortic valveof diseases included within virtually all elds of medic
ineof diseases included within virtually all elds of medicine disease,bounding pulse in the hypertensive andand surgery share a common feature:their etiolog
y orand surgery share a common feature:their etiology or wheeze of the patient with emphysema all igniteclinical presentation results from abnormal mechano
trans-clinical presentation results from abnormal mechanotrans- reexive clinical responses in the mind of the skilledduction. This process may b
e altered by changes in cell
duction. This process may be altered by changes in cell physician,and sometimes even lead to immediatemechanics, variations in extracellular matrix structure,
or bymechanics, variations in extracellular matrix structure, or by diagnoses.deregulation of the molecular mechanisms by which cell
sderegulation of the molecular mechanisms by which cells But in the current genome euphoria,there appearssense mechanical signals and convert them into a c
hemicalsense mechanical signals and convert them into a chemical to be no place for `physicality'. This is especiallyor electrical response. Molecules that mediate mechano
-or electrical response. Molecules that mediate mechano- worrisome given that abnormal cell and tissuetransduction, including extracellular matrix molecules,transduction, including extracellular matrix molecules, responses to mechanical stress contribute to thetransmembrane integrin receptors, cytoskeletal struct
urestransmembrane integrin receptors, cytoskeletal structures etiology and clinical presentation of many importantand associated signal transduction components, may t
here-and associated signal transduction components, may there- diseases,including asthma,osteoporosis,athero-fore represent targets for therapeutic intervention in afore represent targets for therapeutic intervention in a sclerosis,diabetes,stroke and heart failure. There isvariety of diseases. Insights into the mechanical basi
s ofvariety of diseases. Insights into the mechanical basis of also a strong mechanical basis for many generalizedtissue regulation also may lead to development of imp
rovedtissue regulation also may lead to development of improved medical disabilities,such as lower back pain andmedical devices, engineered tissues, and biological
ly-medical devices, engineered tissues, and biologically- irritable bowel syndrome,which are responsible for ainspired materials for tissue repair and reconstruction.inspire
d materials for tissue repair and reconstruction. major share of healthcare costs world-wide. In fact,Keywords: c y tos k el eto n; di s eas e; extra c ell u la r matr ix; i n tegri n ; mec ha ni c al surgeons sometimes even use mechanical forces asforc e s; mec h an otra ns du c ti on; s tre ss - ac ti v ated i on c h an nel s ; t is s ue e ngi n eeri ng therapeutics,such as when traction forces are used to
accelerate bone healing. However,what is missing isAnn Med 2003; 35: 114how these physical interventions could inuence cell
and tissue function,or how altered cell or tissue
mechanics may contribute to disease development.From the Vascular Biology Program,Departments of Surgeryand Pathology,Children's Hospital and Harvard Medical School, In this article,I rst review the fundamental roleBoston,MA 02115,USA. that physical forces and changes in tissue mechanics
Correspondence: Donald E Ingber,MD,PhD,Children'splay in normal development and physiology. I then
Hospital,Enders 1007,300 Longwood Avenue,Boston,MAdescribe recent advances in our understanding of02115,USA. Fax: 617-232-7914. E-mail: [email protected] mechanotransduction,the molecular mech-harvard.edu
# 2003 Taylor & Francis. ISSN 0785-3890DOI 10.1080/07853890310016333 Annals of Medicine 35
T&F -:- FULL SGML TEXT -:- Annals of Medicine MS. 149 Op. PGW {F2-PDF}
N:/SANN/149/149.3D Produced: 24/07/2003 At: 14:38:57
Page Count:14 Page Range:114 Page:1
2 I
NGBER
Key messagesAbbreviations and acronyms
Mechanical forces are critical regulators of.ECM extracellular matrix
cellular biochemistry and gene expression asICAM intercellualr adhesion moleculewell as tissue development.PDGF platelet-derived growth factor
RGD argine-glycine-aspartate Mechanotransduction the process by which.3D three-dimensional
cells sense and respond to mechanical signals
is mediated by extracellular matrix, transmem-
brane integrin receptors, cytoskeletal structuresanism by which cells sense and respond to mechanical and associated signaling molecules.signals. Finally,I explain how the clinical manifesta-
Many ostensibly unrelated diseases share the.tions of many ostensibly unrelated diseases similarly
common feature that their etiology or clinicalresult from abnormal mechanotransduction,and how
presentation results from abnormal mechano-this insight may lead to new avenues for therapeutic
transduction. Mechanotransduction may beintervention.altered through changes in cell mechanics,
extracellular matrix structure or by deregulation
of the molecular mechanisms by which cellsMechanobiology sense mechanical signals or convert them into a
chemical response.In biology and medicine,we tend to focus on the
Molecules that mediate mechanotransduction.importance of genes and chemical factors for controlmay represent future targets for therapeutic
of tissue physiology and the development of disease,intervention in a variety of diseases. Insights
whereas we commonly ignore physical factors. This isinto the mechanical basis of tissue regulationinteresting because it was common knowledge at thealso may lead to development of improvedturn of the last century that mechanical forces aremedical devices, engineered tissues, and biomi-critical regulators in biology (1). Wolff's law describ-metic materials for tissue repair and reconstruc-ing that bone remodels along lines of stress was
published in 1892 (2). However,the advent of more tion.
reductionist approaches in the basic sciences,and the
demonstration of their power to advance under-
standing of the molecular basis of disease,led to a
loss of interest in mechanics. example,are composed of several organs (e.g.,bone,
Although it has received much less attention than muscle) that are constructed by combining variousthe genomics revolution,there has been a renaissance tissues (e.g.,bone,muscle,connective tissue,vascular
in the eld of mechanobiology over the past two endothelium,nerve). These tissues,in turn,are
decades. Physiologists and clinicians now recognize composed of groups of living cells held together by
the importance of mechanical forces for the develop- an extracellular matrix (ECM) comprised of a net-work of collagens,glycoproteins,and proteoglycans.ment and function of the heart and lung,the growthEach cell contains a surface membrane,intracellularof skin and muscle,the maintenance of cartilage and
bone,and the etiology of many debilitating diseases. organelles,a nucleus,and a lamentous cytoskeleton
Exploration of basic mechanisms of sensation and that connects all these elements and is permeated by a
autonomic control,including hearing,balance,touch, viscous cytosol. Each of these subcellular components
and peristalsis,also has demanded explanation in is,in turn,composed of clusters of different mol-
mechanical terms. At the same time,biologists have ecules. In other words,our bodies are complex
come to recognize that mechanical forces serve as hierarchical structures,and hence mechanical defor-important regulators at the cell and molecular levels, mation of whole tissues results in coordinated
and that they are equally potent as chemical cues. For structural rearrangements on many different size
example,cell-generated tensional forces have been scales.
shown to regulate diverse functions,ranging from To understand how individual cells experience
chromosome movements and cell proliferation to mechanical forces,we therefore must rst identify
tissue morphogenesis,in addition to cell contractility the path by which these stresses are transmitted
and motility (35). through tissues and across the cell surface. As in any
To explain mechanoregulation,we must take into three-dimensional (3D) structure,mechanical loads
account that living organisms,such as man,are will be transmitted across structural elements that are
constructed from tiers of systems within systems physically interconnected. Thus,forces that are
within systems (4,6,7). Our arms and legs, for applied to the entire organism (e.g.,due to gravity
# 2003 Taylor & Francis. ISSN 0785-3890 Annals of Medicine 35
T&F -:- FULL SGML TEXT -:- Annals of Medicine MS. 149 Op. PGW {F2-PDF}
N:/SANN/149/149.3D Produced: 24/07/2003 At: 14:39:21
Page Count:14 Page Range:114 Page:2
-
7/29/2019 Mechano Biology
2/14
D 3ISEASES OF MECHANOTRANSDUCTION
or movement) or to individual tissues would be integrins that link to the internal cytoskeleton provide
distributed to individual cells via their adhesions to a much greater degree of mechanical coupling across
the ECM support scaffolds (basement membranes, the cell surface as measured by an increased strength-
interstitial matrix,cartilage,bone) that link cells and ening (stiffening) response when compared with
tissues throughout the body. This can be seen in transmembrane growth factor receptors,histocom-
specialized mechanosensory organs that recognize patibility antigens,or metabolic receptors.
and respond to physical stimuli. In the vestibular Thus,integrins appear to function as cell surface
apparatus,for example,the otoliths (dense calcareous `mechanoreceptors' in that they are among the rst
crystals) mediate sensation of linear acceleration due molecules to sense a mechanical stress applied at theto gravity by deforming a specialized bilaminar ECM. cell surface,and they transmit this signal across the
Local distortion of this ECM activates sensory plasma membrane and to the cytoskeleton over a
neurons within adjacent hair cells by transferring specic molecular pathway. Cell-cell adhesion mol-
mechanical forces across the cell surface and thereby ecules,such as cadherins and selectins,may provide a
inducing bending of cytoskeletal stereocilia that similar mechanical coupling function between the
extend from the cell surface (8). ECM similarly cytoskeletons of neighboring cells (1821). Interest-
mediates mechanical energy transfer to sensory cells ingly,even forces that produce generalized celldistortion,such as apical uid shear stresses inwithin muscle stretch receptors (9).
The mechanical properties of the ECM also endothelium,eventually distribute the stress through
contribute signicantly to the cellular mechanotrans- the cytoskeleton and to integrins within the cell's
duction response. For instance,the high exibility of basal focal adhesions,and to cell-cell adhesion mol-
the ECM of Pacinian corpuscle mechanoreceptor cells ecules at the lateral cell borders (22,23).
in skin ensures that rapid deformations will be sensed,
whereas sustained stresses will dissipate before they
reach the cell (10). This mechanism is used to lter out Force-induced changes in cell structure andsustained signals due to continuous pressure or touch mechanics(e.g.,when we sit and write on the computer for
extend periods of time) a common form of To understand the physiological mechanism by which
receptor adaptation. If the ECM is less exible,then cells respond to mechanical stress,we must rst
stresses will be transmitted to and through the cell, consider how forces impact the cell once they are
only to be dissipated through movements in the transmitted across transmembrane adhesion recep-
cytoskeleton,as observed in stereocilia in hair cells. tors. When most of the readers of this article went to
ECM plays a similar role in mechanoregulation in medical school,they learned that cells are composed
all solid tissues. These molecular scaffolds distribute of a viscous cytosol surrounded by a membrane,with
stresses throughout tissues and focus these forces on a nucleus in its center. With this view of cellsites of cell-ECM adhesion. Cells adhere to ECM architecture,it is difcult to understand how mech-
through binding of specic cell surface receptors. The anical forces could modulate intracellular structure or
most ubiquitous and well characterized class of ECM biochemistry. Over the past quarter century,how-
receptors are known as integrins'. Over 20 different ever,our view of cell structure has changed comple-types of these dimeric protein receptors exist; their tely. We now recognize that living cells contain abinding specicity (e.g.,for collagen versus bronec- cytoskeleton. This is an internal molecular frame-tin) depends on the specic pairing combination of work or lattice composed of three different types of
interacting a and b subunits (11,12). The external molecular laments (microlaments,microtubules
portion of these transmembrane receptors binds to and intermediate laments) that provides shape
specic peptide sequences (e.g.,RGD) in ECM mol- stability to the cell (24). However,the cytoskeleton
ecules,while their intracellular domains physically is not simply a passive gel. All cells generate tensional
associate with actin-associated proteins and thereby, forces through actomyosin lament sliding in theirform a molecular bridge between the ECM and the cytoskeleton. These tensional forces are resisted and
cytoskeleton. Integrins are not evenly distributed in balanced by external adhesions to ECM and neigh-
the membrane,rather they cluster together within boring cells,and by other molecular laments (e.g.,
specialized anchoring complexes known as focal microtubules) that locally resist inward-directed
adhesions' (13). tensional forces inside the cytoskeleton.
Importantly,integrins provide a preferred site for This type of force balance is a hallmark of an
mechanical signal transfer across the cell surface, architectural system known as tensegrity',and
when compared with other types of transmembrane computational models based on tensegrity theory
receptors. This has been demonstrated directly by can predict complex mechanical behaviors of mam-
applying mechanical forces to surface membrane malian cells (7,2426). Thus, the cell does not
receptors of cultured cells (1417). Cell surface respond to mechanical stress like a balloon lled
# 2003 Taylor & Francis. ISSN 0785-3890 Annals of Medicine 35
T&F -:- FULL SGML TEXT -:- Annals of Medicine MS. 149 Op. PGW {F2-PDF}
N:/SANN/149/149.3D Produced: 24/07/2003 At: 14:39:22
Page Count:14 Page Range:114 Page:3
-
7/29/2019 Mechano Biology
3/14
4 I
NGBER
with molasses or jello'. Instead,the viscoelastic Starling curve exhibited by the whole heart. Cell
behavior of living cells results from collective mech- shape-dependent changes in the sensitivity of the
anical interactions within the tensed molecular contractile machinery may ensure compliance match-
cytoskeleton. Cytoskeletal forces are also harnessed ing' in muscle cells of the gastrointestinal tract,
to transport organelles (e.g.,mitochondria,synaptic genitourinary system,pulmonary airways,blood
vesicles) in the cytoplasm,to move chromosomes vessels and heart,as well as in epithelial and
during mitosis,and as long recognized in muscle,to connective tissues,so that the level of tension exerted
generate tensional forces that are important for cell by the cell precisely balances the mechanical stress
contractility as well as movement. The effects of transmitted through the surrounding ECM inapplied stresses on cell shape and mechanics will response to tissue distortion.
therefore depend on the material properties of the In summary,these studies have revealed that the
cytoskeletal laments,their organization (architec- physicality of the ECM substrate and degree of cell
ture),and the level of isometric tension or prestress' distortion govern cell behavior regardless of the
in the cell,much like the mechanical responsiveness of presence of hormones,cytokines or other soluble
whole muscle is governed by its structural organiza- regulatory factors. Local alterations in ECM structure
tion and by its contractile tone. Because individual that inuence cell shape and mechanics,such asthinning of basement membrane produced bycells (both muscle and non-muscle) apply tractional
forces on their adhesions,cultured cells spread and increased ECM turnover (e.g.,metalloproteinase
atten on rigid ECM substrates,whereas they retract activities),also appear to drive regional changes in
and round on exible ECMs. cell growth and motility during tissue development
(25,42). Lung branching morphogenesis in the
embryo can be selectively inhibited or accelerated by
decreasing or increasing cytoskeletal tension,respec-Mechanical determinants of cell andtively,using pharmacological agents (43). Regionaldevelopmental controlchanges in ECM structure and associated changes in
What may be most surprising is that changes in cytoskeletal mechanics similarly contribute to control
microscale forces that alter the cytoskeletal force of angiogenesis that is required for wound healing as
balance and modulate cell shape also control complex well as tumor progression (44). In fact,cell-generated
cell behaviors that are critical for development and tensional forces appear to play a central role in the
tissue homeostasis. Cell growth,differentiation, development of virtually all living tissues and organs
polarity,motility,contractility and programmed cell (24,25,42),even in neural tissues,such as retina (45)
death,all can be inuenced by physical distortion of and brain (46).
cells through their ECM adhesions. For instance, Various in vitro and in vivo studies conrm that
chondrocytes,hepatocytes,mammary epithelium, mechanical forces directly regulate the shape andretinal epithelium,capillary endothelium,and bro- function of essentially all cell types (5). Individual
blasts can be switched from growth to differentiation bone cells increase deposition of bone ECM when
in the presence of soluble mitogens by decreasing the exposed to mechanical stresses with high frequency
stiffness or adhesivity of the ECM,and thereby and low strain in vitro,just as they do within wholebone (47),and differences in mechanical loadingpromoting cell retraction and rounding (2734).conditions can direct bone versus cartilage formationAdherent endothelial cells can be switched from
growth to apoptosis by more fully restricting cell (48). Chondrocytes respond to compressive loading
spreading (35). Varying the mechanical compliance by altering production of proteoglycans that comprise
(exibility) of the ECM also inuences the rate of cell cartilage matrix (49). Skeletal muscle cells increase
migration (36) and the direction of motility can be their mass,upregulate expression of muscle-specic
affected by geometric cues from the ECM (37). Direct proteins and even organize into muscle fascicles in
application of tensional forces to cultured endothelial vitro when stretched with physiologically relevantcells similarly promotes capillary outgrowth in 3D load cycles (50,51); heart cells increase secretion of
collagen gels (38) and nerve cells respond to tensional atrial natriuretic factor (52). Skin epithelium,bone
forces exerted on their surfaces by extending nerve cells,broblasts,and embryonic heart muscle cells all
processes in the direction of the applied stress (39). increase their growth rates when they experience
Changing vascular smooth muscle cell shape through mechanical strain (5356),whereas stretch induces
modulation of cell-ECM adhesion or alteration of differentiation in periodontal ligament cells (57).
ECM compliance also regulates its contractile Endothelium sense uid shear stresses and respond
response to vasoagonists,such as endothelin-1 (40, by altering their expression of proteins that are
41). In fact,individual cultured vascular smooth involved in lymphocyte binding (e.g.,ICAM),tissue
muscle cells display a bell-shaped,force-length remodeling (e.g.,PDGF) and handling oxidant stress,
relationship (40) that is highly reminiscent of the and some of these effects are mediated through
# 2003 Taylor & Francis. ISSN 0785-3890 Annals of Medicine 35
T&F -:- FULL SGML TEXT -:- Annals of Medicine MS. 149 Op. PGW {F2-PDF}
N:/SANN/149/149.3D Produced: 24/07/2003 At: 14:39:22
Page Count:14 Page Range:114 Page:4
-
7/29/2019 Mechano Biology
4/14
D 5ISEASES OF MECHANOTRANSDUCTION
activation of specic shear stress-response elements' cultured cells are mechanically stressed,the cell
in certain gene promoters (58,59). Kidney epithelial responds by increasing recruitment of focal adhesion
cells respond to levels of uid shear similar to those (cytoskeletal linker) proteins and mechanically
produced by urine ow in collecting ducts by strengthening itself against additional stress (14
increasing calcium inux (60,61). Changes in gene 17,6870). When the same stress is applied to other
expression and growth of bladder smooth muscle cells transmembrane receptors that do not mediate cell
that are triggered by outlet obstruction appear to adhesion,there is very little response. Because
result from mechanical stretch secondary to over- integrins preferentially mediate mechanical signal
lling of the bladder (62). Glomerular ltration rate is transfer across the cell surface,the molecular compo-similarly controlled by alterations in vasomotor tone nents of the cytoskeletal scaffolds that connect to
of preglomerular,glomerular,and postglomerular integrins within the focal adhesion will experience
microvessels,as well as associated changes in mesan- increased mechanical stress whereas soluble compo-
gial cell contractility (63). During pregnancy,the nents in the nearby cytosol will not. For example,
onset of labor is triggered by distention of the uterus when large-scale deforming forces are applied to
imposed by the growing fetus (64),and pulmonary integrins,cytoskeletal laments and linked intra-
epithelial cells increase secretion of surfactant when nuclear structures can be seen to realign along theapplied tension eld lines (71,72). Application of uidstretched in vitro (65),just as they do in a newborn
when it takes its rst breath. shear stress to the apical membrane of vascular
endothelium similarly results in distortion of cyto-
skeletal laments throughout the cell (73) as well as
funneling of stress along this load-bearing network inCellular mechanotransductionthe cytoplasm all the way to the cell's basal ECM
But how do mechanical forces in uence cellular adhesions (22,23). Kidney epithelium senses shear
biochemistry and gene expression so as to produce stress through deformation of the primary cilium (60,
these varied effects on cell and tissue behavior? This 61). This is a single,specialized,cytoskeletal process
mechanism is difcult to envision because it does not that extends vertically from the apical cell surface and
involve a classic stimulus-response' coupling as used functions like a long lever arm for the whole
by soluble hormones or secretagogues. In the case of cytoskeleton,much like stereocilia in hair cells of
hormonal stimulation,no molecular signal is present the inner ear.
prior to stimulation and the relevant receptor binding If the cytoskeletal laments and associated regula-
sites are unoccupied. Then when the hormone tory molecules distort without breaking when integ-
stimulus is provided,it binds to its receptor and rins or specialized cytoskeletal extensions (e.g.,
initiates an intracellular signaling response. In con- stereocilia,primary cilia) are stressed,then some or
trast,because cell shape is determined through a all of the molecules that comprise these structuresbalance of mechanical forces (2426),any external must similarly change shape. When the shape of a
mechanical stimulus that impinges on an adherent cell molecule is altered,its biophysical properties (ther-
is imposed on a pre-existing force balance,much like modynamics,kinetics) change,and hence biochem-
pulling an arrow back against a tensed bow-string. istry (e.g.,chemical reaction rates) will be altered(4,74). This is important because many of theThis is important because the pre-existing tensileenzymes and substrates that mediate cellular metab-stress (prestress) or tone in the cell can at times govern
the response' to the mechanical stimulus' (66,67). olism (e.g.,protein synthesis,glycolysis,RNA pro-
In the case of adherent cells,forces applied at the cessing,DNA replication) are physically immobilized
macroscale also will result in changes in ECM and on the cytoskeleton and nuclear matrix (nucleoskele-
cytoskeletal mechanics on the microscale. For exam- ton) (75,76). In particular,many signal transduction
ple,the vessel wall decreases its mechanical compli- molecules are oriented on the cytoskeletal backbone
ance (i.e.,becomes more rigid) when it is physically of the focal adhesion complex at the site of integrindistended due to increased blood pressure. Osmotic binding; these include mechanically-gated ion chan-
forces similarly tense and stiffen interstitial matrix, nels,protein kinases (e.g.,FAK,src),small GTPases,
for example,in cerebral edema or following injury to heterotrimeric G proteins,inositol lipid kinases,and
the liver; pressure overload has a similar effect in the certain growth factor receptors (77,78).
heart. These changes in ECM mechanics will not Experiments conrm that local changes in bio-
transfer force equally to all points on the surface of chemical signal transduction are produced when
neighboring adherent cells. Rather,a tug on the ECM external forces are applied to integrins. The increased
will be felt by the cell through its focal adhesions and recruitment of focal adhesion proteins and associated
hence,through its transmembrane integrin receptors cytoskeletal strengthening response that result when
that link to the cytoskeleton. integrins are stressed (1417,79) are mediated by
When integrins on the surface membrane of local activation of the small GTPase Rho and the
# 2003 Taylor & Francis. ISSN 0785-3890 Annals of Medicine 35
T&F -:- FULL SGML TEXT -:- Annals of Medicine MS. 149 Op. PGW {F2-PDF}
N:/SANN/149/149.3D Produced: 24/07/2003 At: 14:39:22
Page Count:14 Page Range:114 Page:5
-
7/29/2019 Mechano Biology
5/14
6 I
NGBER
protein tyrosine kinase,c-src (69,70,79). Mechanical ously activated by subtle variations in ECM structure
stress application to integrins also stimulates rapid within living tissues that are constantly exposed to
(within 10 msec) calcium inux in the neuromuscular physiological stresses. Because forces applied locally
synapse (due to rapid muscle twitching) (80),recruits through integrins also produce coordinated deforma-
the protein synthetic machinery to the site of force tion of molecular structures throughout the cyto-
application (81),and activates cAMP signaling within skeleton and nucleus (71,72), mechanochemical
the focal adhesion which eventually leads to stress- transduction could occur at distant or multiple sites
induced changes in gene transcription (82). Stress in the cell. In fact,application of mechanical stress to
application through integrins induces endothelin-1 integrins can produce the same focal adhesiongene expression in endothelial cells and this response signaling response (e.g.,production of cAMP) in
can be prevented by dissipating cytoskeletal tension round versus spread cells (82),however,the cells that
(prestress) and hence,altering cell mechanics (66,67). are globally distorted proliferate whereas the round
Again,application of similar mechanical stresses to cells undergo apoptosis (35). As described above,the
other transmembrane receptors that are not adhesion global shape of the cell dictates its behavior (e.g.,
receptors fails to produce these responses. Other growth versus differentiation or apoptosis),and these
signaling molecules that have been shown to be effects are mediated through tension-dependentchanges in cytoskeletal structure and mechanicsactivated by mechanical stress in an integrin-depen-
dent manner in various cell types include protein (37,100,101). Thus, cells appear to think globally'
tyrosine kinases (FAK,src),Shc,ERK1/2,protein in that large-scale mechanical distortion of cell shape
kinase C,PI-3-kinase,Akt,small GTPases (Rho, and the cytoskeleton govern how the cell processes
Rac),heterotrimeric G proteins,paxillin,SREBP1, and integrates locally-elicited signals (mechanical as
hsp 27 and b-catenin (70,79,8291). well as chemical) to produce a concerted behavioral
Importantly,all cells also contain stress-sensitive' response (74).
(mechanically-gated) ion channels that either increase
or decrease ion ux when their membranes are
mechanically stressed (92,93). For example, specia- Implications for clinical medicinelized mechanosensory `hair' cells of the inner ear
detect sound through de ections of their stereocilia These new insights into mechanobiology suggest that
that result in the opening of mechanosensitive cation many ostensibly unrelated diseases may share a
channels. Direction- and amplitude-dependent depo- common dependence on abnormal mechanotransduc-
larizations caused by these de ections result in tion for their development or clinical presentation.
induced currents that are relayed to nerve bers Mechanotransduction may be altered through
(94). The vestibular system relies on similar hair cells changes in cell mechanics,ECM structure or by
at the base of the semicircular canals to sense three- deregulation of the molecular mechanisms by whichdimensional rotation through uid ow; linear accel- cells sense mechanical signals or convert them into a
erations are sensed in the utricle and saccuole through chemical response. In fact,physicians in almost every
deection of mineral deposits (otoconia) within a branch of medicine and surgery care for patients who
specialized ECM (otolithic membrane) that again tugs have ailments that may be viewed as diseases ofon stereocilia within adjacent hair cells (95). Stretch- mechanotransduction,as discussed below and sum-sensitive channels at the sensory neuron terminals marized in Table 1.located under the epidermis and hair follicles also Although the question of how cells determine their
mediate touch sensation,and related mechanisms are shape and mechanics may seem esoteric,the reality is
used for pressure and stretch sensation as well as that it has important clinical implications. For
proprioception (96,97). However,even the function example,leukocytes physically deform when they
of these specialized mechano-electrical transducers pass through pulmonary capillary beds (102) and
appears to depend on their linkage to the cytoskeleton inammatory agents that increase cytoskeletal stiff-and hence,indirectly on integrin coupling to the ECM ness in circulating neutrophils induce leukocyte
(93,98) which stabilizes the entire cytoskeleton sequestration in the lung (103). The ability of tumor
against shape distortion (24). For readers interested cells to resist traumatic destruction in the vasculature,
in molecular mechanisms of mechanotransduction, and hence their ability to metastasize and survive in
more detailed discussions can be found in various distant capillary beds,depends on their exibility
recent reviews (4,5,47,85,95,98,99). (104). The effectiveness of delivery of therapeutic
In biology,we emphasize linear thinking and focus cytotoxic lymphocytes into tumor tissues similarly
on local molecular binding and assembly events. But if can vary with their stiffness (105). Mechanical
all mechanosensing was carried out locally at the site stretching of kidney mesangial cells through integrins
where stresses impinge on the surface membrane (e.g., due to glomerular hypertension represents a common
in the focal adhesion),then cells would be continu- nal pathway for glomerulosclerosis (106107),and
# 2003 Taylor & Francis. ISSN 0785-3890 Annals of Medicine 35
T&F -:- FULL SGML TEXT -:- Annals of Medicine MS. 149 Op. PGW {F2-PDF}
N:/SANN/149/149.3D Produced: 24/07/2003 At: 14:39:23
Page Count:14 Page Range:114 Page:6
-
7/29/2019 Mechano Biology
6/14
D 7ISEASES OF MECHANOTRANSDUCTION
Table 1. Diseases of mechanotransduction
Cardiology Angina (vasospasm) C T
Atherosclerosis T M
Atrial brillation M
Heart failure C T M?
Hypertension C T M?
Intimal hyperplasia C T M?
Valve disease T
Dermatology Scleroderma T
Gastroenterology Achalasia C
Irritable bowel syndrome C M?
Volvulus C T
Nephrology Diabetic nephropathyC T M?
Glomerulosclerosis C T M?
Neurology Cerebral edema T
Facial tics C
Hydrocephalus T C?
Migraine C M?
Stroke C T
Stuttering C
Oncology Cancer C T M?
Metastasis C
Opthalmology Glaucoma C T M?
Orthopedics Ankylosing spondylitis C T
Carpal tunnel syndrome C T
Chronic back pain C T
Dupytren's contracture C T
Osteoporosis T M
Osteoarthritis T
Rheumatoid arthritis T
Pediatrics Collagenopathies T
Congenital deafness C T M
Mucopolysaccharidoses T
Musculodystrophies C T M
Osteochondroplasias C T
Polycystic kidney disease T M
Pulmonaryhypertension of newborn C T M?
Pulmonary medicine ARDS C T M
Asthma C T M?
Emphysema T
Pulmonarybrosis T
Pulmonaryhypertension C T M?
Ventilator InjuryC M
Reproductive medicine Pre-eclampsia C T M?
Sexual dysfunction (male & female) C M?
Urology Urinaryfrequency/incontinence C M?
A partial list of diseases that share the feature that their etiologyor clinical presentation results from abnormal mechanotransduction.
The right column indicates whether the mechanical basis of the disease or condition is likelydue to changes in cell mechanics (C),
alterations in tissue structure (T), or deregulation of mechanochemical conversion (M); ?' indicates situations where deregulation of
mechanochemical conversion is likelybut remains to be demonstrated.
altered cell mechanics contributes to the clinical pulmonary hypertension of the newborn,broncho-presentation of asthma and other pulmonary diseases pulmonary dysplasia,asthma,achalasia,preeclamp-
(108). Even some of the genetic causes of deafness sia,urinary frequency,irritable bowel syndrome,and
involve mutations in cytoskeletal proteins,such many causes of chronic back pain,are all based on
myosin,espin and mDia,that alter hair cell mechanics muscle cell hypercontractility. Dupytren's contracture
(109111),and certain patients with autoimmune ear is characterized by hypercontractility of ligamental
disease have antibodies directed against b-actin (112). broblasts (114),whereas glaucoma (115) and hydro-
Mutations in specialized ECM proteins and deletion cephalus (116) result from physical constrictions that
of integrin a8b1,which is found in hair cells,also obstruct uid ow in the eye and cerebrospinal space,
hinders stereocilia maturation and hair cell differ- respectively. Recent studies suggest that genetic
entiation (113). mutations or malfunction of cytoskeletal proteins,
Systemic and pulmonary hypertension,persistent ECM molecules or integrins that alter cell and tissue
# 2003 Taylor & Francis. ISSN 0785-3890 Annals of Medicine 35
T&F -:- FULL SGML TEXT -:- Annals of Medicine MS. 149 Op. PGW {F2-PDF}
N:/SANN/149/149.3D Produced: 24/07/2003 At: 14:39:24
Page Count:14 Page Range:114 Page:7
-
7/29/2019 Mechano Biology
7/14
8 I
NGBER
mechanics can lead to impaired vascular smooth appears to be controlled by metalloproteinases that
muscle and cardiac muscle contractility,as well as structurally remodel ECM (139).
various forms of heart disease (119121). In fact,most Other diseases result directly from deregulation of
of the molecular causes of heart failure appear to transmembrane mechanical signaling. Atrial brilla-
disrupt the biomechanical balance between the tion may be caused by abnormal conversion of
cytoskeleton,membrane,and ECM (122). In contrast, mechanical stress gradients (e.g.,secondary to volume
decreased smooth muscle cell contractility results in overload) into intracellular gradients of electrical
urinary stress incontinence (123),as well as defects in activity as a specic peptide inhibitor of stress-
male and female sexual function (124,125). Abnormal activated ion channels can prevent the heartbeat frommuscle tone also can lead to destabilization of the losing its rhythm (140). Dystrophin,the gene product
skeleton (126) and contribute to skeletal and joint that is mutated in Duchenne's muscular dystrophy is
diseases. For example,axial muscular dysfunction has part of the specialized focal adhesion (dystroglycan)
been implicated in the development of joint pathology complex that mechanically couples the cytoskeleton
in ankylosing spondylitis (127). to ECM in skeletal muscle (141). Mutations in various
In other conditions,mechanotransduction may be load-bearing molecules in muscle,including other
compromised as a result of changes in ECM forma- adhesion complex proteins,integrins,or ECM pro-
tion or remodeling. Many genetic diseases and teins,lead to development of similar musculardevelopmental disabilities,including various osteo- dystrophies (130,141143). Moreover, cells with
chondrodysplasias,mucopolysaccharidoses and col- these mutations exhibit abnormal responses to mech-
lagenopathies are essentially disorders of connective anical stress,as well as altered cell and cytoskeletal
tissue structure and mechanics (128,129). In one mechanics (143145). Kidney duct epithelial cells
form of muscular dystrophy,a mutation in an ECM from transgenic mice that lack functional polycystin
protein (laminin a2) leads to both the muscular 1,and hence develop autosomal dominant polycystic
degeneration and sensineural hearing loss that are kidney disease,fail to increase calcium inux in
observed in many patients with this disease (130). A response to uid shear stresses when applied at levels
mutation in a brillar collagen gene (COL11A1) similar to those that occur in vivo (60,61). If
produces chondrodyplasia when homozygous,and collecting ducts utilize a mechanical control mechan-
both osteoarthritis and hearing loss when hetero- ism similar to that of blood vessels which increase
zygous. Patients with Stickler syndrome and Mar- their diameter when hemodynamic shear stresses rise
shall syndrome are also heterozygous for mutations (58),then loss of this normal homeostatic mechanism
in this gene (131). Abnormal brillin deposition in could lead to unregulated duct expansion and hence
patients with Marfan's syndrome alters the vascular cyst formation. Osteoporosis also may be caused by
endothelial cell response to hemodynamic stresses aberrant mechanotransduction since similar bone loss
and results in aortic dissection due to local weakness can result from mechanical unloading,for example,of the vascular wall (132). Accumulation of abnormal due to extended bed rest or exposure to microgravity
ECM also contributes to development of abnormal (146). Interestingly,certain osteoporosis drugs speci-
tissue mechanics and clinical compromise of function cally target integrin receptors that mediate mechan-
in patients with scleroderma,pulmonary brosis, otransduction (147). Other conditions that may resultvascular hypertension,and diabetic nephropathy, from stretch-activated signaling cascades include
whereas emphysema is characterized by enhanced development of intimal hyperplasia induced by stent
ECM breakdown. Although rheumatoid arthritis has placement in coronary arteries or by replacement of
an inammatory basis,joint pain and reduced constricted vessels with arteriovenous grafts (148),
movement are also due to the breakdown of the and ventilation-induced lung injury (e.g.,ARDS)
cartilage matrix. In fact,angiogenesis inhibitors that (149).
prevent cartilage matrix dissolution by inhibiting Recognition of the importance of mechanics and
capillary invasion can signicantly suppress the cellular mechanotransduction for tissue developmentclinical and histological symptoms of rheumatoid also may help to explain the focal incidence of disease.
arthritis in an animal model without evidence of Although high cholesterol and LDL promote athero-
immunosuppression (133). Changes in ECM struc- sclerotic plaque formation,these plaques preferen-
ture that alter tissue mechanics and provide a tially form in regions of disturbed blood ow (e.g.,
constitutive stimulus for cell growth may even near vessel branches) (58). Thus,if one could under-
contribute to cancer initiation and progression stand how cells sense ow,it might be possible to
(134136). For example,overexpression of an prevent plaque formation in the future. Local changes
ECM-degrading enzyme in transgenic mice results in tissue structure also may explain why genetic
in formation of malignant tumors (136,137). The diseases,including cancer,often present focally (e.g.,
`angiogenic switch' that initiates tumor angiogenesis retinoblastoma usually only occurs in one eye). In
and is required for cancer formation (138) also other words,changes in tissue mechanics may
# 2003 Taylor & Francis. ISSN 0785-3890 Annals of Medicine 35
T&F -:- FULL SGML TEXT -:- Annals of Medicine MS. 149 Op. PGW {F2-PDF}
N:/SANN/149/149.3D Produced: 24/07/2003 At: 14:39:24
Page Count:14 Page Range:114 Page:8
-
7/29/2019 Mechano Biology
8/14
D 9ISEASES OF MECHANOTRANSDUCTION
common feature in many diseases may explain why aTable 2. Mechanical therapies
toxin that modulates cell tension Botulinum AAcupuncture
(Botox) is being tested as a treatment for a wideAnti-arrhythmic drugs
range of ailments,including stroke paralysis,Anti-spasmodic drugsmigraine headaches,facial tics,stuttering,lower backBone fracture healing
pain,incontinence,carpal tunnel syndrome and tennisBotoxCardiac perfusion elbow,in addition to being a high priced cosmeticDistraction osteogenesis
(156). Another chemical inhibitor of cell tension thatInotropic drugs
targets Rho-associated kinase,a molecule that bothLung ventilationmediates mechanosignaling through integrins andMassage therapy
regulates cytoskeletal contractility (69,70), also hasMuscle relaxantsOrthodontics been found to prevent disease progression in experi-Physical therapy
mental models of glaucoma (157) and intimalRho-kinase inhibitor (fasudil)hyperplasia (158). Importantly,one form of thisStentscompound,fasudil,appears to be useful for treatmentSurfactant
Tissue engineering (manufacturing process) of systemic hypertension (159) as well as angina dueTissue expansion (e.g., breast) to myocardial ischemia in humans (160). Conven-Vasodilators
tional vasodilators,muscle relaxants,inotropic agentsVentilator therapy
and anti-spasmodic drugs similarly prevent clinicalWound closure (e.g., vacuum-assisted)symptoms based on their ability to modulate cell
A partial list of clinical therapies that are currentlyin use or inmechanics,and anti-arrythmics directly modulate
development whose action is largelybased on altering cell and mechano-electrical conversion in heart cells. Thetissue mechanics, or directlyaltering cellularfunction of cardiac perfusion devices is also purelymechanotransduction (see text for details).mechanical. However,even complex developmental
processes,such as angiogenesis,can be controlled by
contribute signicantly to the epigenetic basis of altering cell and tissue mechanics,for example,using
disease. drugs that target the cytoskeleton (161,162),integrins
Understanding of the relation between structure (163) or the ECM (164166). Some of these drugs have
and function in living tissues and of fundamental entered human clinical trials for angiogenesis-depen-
mechanisms of cellular mechanotransduction may dent diseases,such as cancer and macular degenera-
therefore lead to entirely new modes of therapeutic tion. Thus,someday it may be possible to treat a huge
intervention (Table 2). In fact,surgeons already use range of diseases using drugs that specically target
mechanical therapies to promote tissue growth and molecules that contribute to mechanoregulation. In
remodeling. Examples include the use of surfactant to the eld of tissue engineering,mechanical forcepromote lung development in premature infants regimens also have been integrated into device
(150),mechanical ventilation with low tidal volume fabrication protocols. Engineered tissues,including
to decrease morbidity and death in patients with acute articial blood vessels,skeletal muscle,cardiac
lung injury and acute respiratory distress syndrome muscle and heart valve,greatly increase their mech-anical strength and clinical efcacy if preconditioned(ARDS)(151),expandable stents to physically prevent
coronary artery constriction (152),tissue expanders to using force regimens prior to implantation (167171).
increase the skin area available for reconstruction of Design and fabrication of synthetic `biomimetic'
large surface defects,and devices for tension applica- biomaterials and nanotechnologies that mimic the
tion for distraction osteogenesis,orthodontics,bone mechanical as well as chemical properties of natural
fracture healing,craniofacial surgery,cosmetic breast tissue structures may revolutionize the medical device
expansion and closure of non-healing wounds (153, industry in the future.
154). These devices are believed to act throughalterations in microscale forces (e.g.,cell stretching)
that activate cellular signal transduction (153,154). ConclusionThe therapeutic value of physical therapy,massage,
and muscle stimulation is also well known. But even The current focus in medicine is on the genetic basis
the effects of acupuncture therapy on pain control and of disease. However,it is not necessary to correct the
other clinical symptoms appear to result from underlying genetic defect in order to treat clinically
physical manipulation (twisting) of the needles that relevant symptoms or relieve the pain and morbidity
produces ECM distortion and associated integrin- of disease. Moreover,most of the clinical problems
dependent changes in cellular mechanotransduction that bring a patient to the doctor's ofce result from
(155). changes in tissue structure and mechanics. Although
The nding that abnormal cell contractility is a these physical alterations have been commonly
# 2003 Taylor & Francis. ISSN 0785-3890 Annals of Medicine 35
T&F -:- FULL SGML TEXT -:- Annals of Medicine MS. 149 Op. PGW {F2-PDF}
N:/SANN/149/149.3D Produced: 24/07/2003 At: 14:39:25
Page Count:14 Page Range:114 Page:9
-
7/29/2019 Mechano Biology
9/14
10 I
NGBER
viewed as the end-result of the disease process,recent The value of macroscale forces as therapeutics has
advances in mechanobiology suggest that abnormal already been demonstrated by surgeons,however,the
cell and tissue responses to mechanical stress may potential clinical value of developing approaches to
actively contribute to the development of many selectively control microscale forces may be even
diseases and ailments. Thus,it might be wise to greater. Pursuit of the relation between structure and
search for a physical cause when chemical or mol- function at the molecular scale in living cells and
ecular forms of investigation do not sufce. tissues also may lead to the development of entirely
These observations also raise the possibility that new biomaterials and microdevices for repair and
the molecules that mediate mechanotransduction, replacement of injured tissues. Thus,if we are toincluding ECM molecules,cell surface adhesion advance patient care in the twenty rst century,we
receptors,cytoskeletal components,and related signal need to do more than delineate the genetic causes of
transduction molecules may represent future targets disease; we also must reintegrate mechanics into our
for therapeutic intervention in a variety of diseases. understanding of the molecular basis of disease.
References
1. Thompson DW. On Growth and Form. 2 edn. London: 19. Yoshida M, Westlin W F, Wang N, Ingber DE, Rosenweign d
Cambridge University Press; 1952. A, Resnick N, et al. Leukocyte adhesion to vascular2. Wolff Y. Das Gesetz der Transformation der Knochen. endothelium induces e-selectin association with the actin
Berlin 1842. cytoskeleton. J Cell Biol 1996; 133: 44555.
3. Ingber DE. Integrins as mechanochemical transducers. Curr 20. Potard US, Butler JP, Wang N. Cytoskeletal mechanics inOpin Cell Biol 1991; 3: 8418. conuent epithelial cells probed through integrins and E-
4. Ingber DE. Tensegrity: the architectural basis of cellular cadherins. Am J Physiol 1997; 272: C165463.mechanotransduction. Annu Rev Physiol 1997; 59: 57599. 21. Ko KS, Arora PD, McCulloch CA. Cadherins mediate
5. Chicurel ME, Chen CS, Ingber DE. Cellular control lies in intercellular mechanical signaling in broblasts by activationthe balance of forces. Curr Opin Cell Biol 1998; 10: 2329. of stretch-sensitive calcium-permeable channels. J Biol Chem
6. Chen CS, Ingber DE. Tensegrity and mechanoregulation: 2001; 276: 3596777.from skeleton to cytoskeleton. Osteoarthritis Cartilage 1999; 22. Davies PF, Robotewskyj A, Griem ML. Quantitative7: 8194. studies of endothelial cell adhesion. Directional remodeling
7. Ingber DE. The architecture of life. Scientic American of focal adhesion sites in response to ow forces. J Clin1998; 278: 4857. Invest 1994; 93: 20318.
8. Kacahr B, Parakkal P, Fex J. Structural basis for mechanical 23. Helmke BP, Rosen AB, Davies PF. Mapping mechanicaltransduction on the frog sensory apparatus: I. The otolithic strain of an endogenous cytoskeletal network in livingmembrane. Hear Res 1990; 45: 17990.
endothelial cells. Biophys J 2003; 84: 26919.9. Wilson LJ, Paul DH. Functional morphology of the telson-
24. Ingber DE, Tensegrity I. Cell structure and hierarchical
uropod stretch receptor in the sand crab Emerita analoga. J systems biology. J Cell Sci 2003; 116: 115773.Comp Neurol 1990; 296: 34358.
25. Ingber DE, Jamieson JD. 1985. Cells as tensegrity struc-10. Dubovy P, Bednarova J. The extracellular matrix of rat
tures: architectural regulation of histodifferentiation byPacinian corpuscles: an analysis of its ne structure. Anat
physical forces tranduced over basement membrane. InEmbryol (Berl) 1999; 200: 61523.
Andersson LC,Gahmberg CG,Ekblom P,eds. Gene11. Ruoslahti E. Integrins. J Clin Invest 1991; 85: 15. Review.
Expression During Normal and Malignant Differentiation.12. Hynes RO. Integrins: bidirectional,allosteric signaling
Orlando: Academic Press; 1985: 1332.machines. Cell 2002; 110: 67387.
26. Ingber DE. Cellular tensegrity: dening new rules of13. Burridge K, Chrzanowska-Wodnicka M. Focal adhesions,
biological design that govern the cytoskeleton. J Cell Scicontractility,and signaling. Annu Rev Cell Dev Biol 1996; 12:
1993; 104: 61327.463518.27. Glowacki J, Trepman E, Folkman J. Cell shape and14. Wang N, Butler J.P, Ingber D. E. Mechanotransduction
phenotypic expression in chondrocytes. Proc Soc Exp Biolacross the cell surface and through the cytoskeleton. ScienceMed 1983; 172: 938.1993; 260: 11247.
28. Li ML, Aggeler J, Farson DA, Hatier C, Hassell J, Bissell15. Schmidt CE, Horwitz A F, Lauffenburger DA, Sheetz M P.
MJ. Inuence of a reconstituted basement membrane and itsIntegrin-cytoskeletal interactions in migrating broblasts arecomponents on casein gene expression and secretion indynamic,asymmetric,and regulated. J Cell Biol 1993; 123:mouse mammary epithelial cells. Proc Natl Acad Sci USA97791.1987; 84: 13640.16. Bausch AR, Ziemann F, Boulbitch AA, Jacobson K,
29. Ben-Ze'ev A, Robinson GS, Bucher NL, Farmer SR. Cell-Sackmann E. Local measurements viscoelastic parameterscell and cell-matrix interactions differentially regulate theof adherent cell surfaces by magnetic bead micro-rheometry.expression of hepatic and cytoskeletal genes in primaryBiophys J 1998; 75: 203849.cultures of rat hepatocytes. Proc Natl Acad Sci USA 1988; 85:17. Alenghat FJ, Fabry B, Tsai K, Goldmann WH, Ingber DE.
21615.Analysis of cell mechanics in single vinculin-decient cells
30. Ingber DE, Folkman J. Mechanochemical switching be-using a magnetic tweezer. Biochem Biophys Res Communtween growth and differentiation during broblast growth2000; 277: 939.factor-stimulated angiogenesis in vitro: role of extracellular18. Wang N, Ingber DE. Probing transmembrane mechanical
coupling and cytomechanics using magnetic twisting cyto- matrix. J Cell Biol 1989; 109: 31730.
metry. Biochem Cell Biol 1995; 73: 32735. 31. Opas M. 1989. Expression of the differentiated phenotype by
# 2003 Taylor & Francis. ISSN 0785-3890 Annals of Medicine 35
T&F -:- FULL SGML TEXT -:- Annals of Medicine MS. 149 Op. PGW {F2-PDF}
N:/SANN/149/149.3D Produced: 24/07/2003 At: 14:39:25
Page Count:14 Page Range:114 Page:10
-
7/29/2019 Mechano Biology
10/14
D 11ISEASES OF MECHANOTRANSDUCTION
epithelial cells in vitro is regulated by both biochemistry and activated atrial natriuretic peptide secretion in atria with
mechanics of the substratum. Dev Biol 131: 28193. heat shock protein 70 overexpression. Exp Biol Med 2003;
32. Mochitate K, Pawelek P, Grinnell F. Stress relaxation of 228: 2006.
contracted collagen gels: disruption of actin lament 53. Ryan TJ. Biochemical consequences of mechanical forces
bundles,release of cell surface bronectin,and down- generated by distention and distortion. J Am Acad Dermatolregulation of DNA and protein synthesis. Exp Cell Res 1989; 21: 11530.1991; 193: 198207. 54. Hatton JP, Pooran M, Li CF, Luzzio C, Hughes-Fulfor M.
33. Singhvi R, Kumar A, Lopez G, Stephanopoulos GN, A short pulse of mechanical force induces gene expressionWang DIC, Whitesides GM, Ingber DE. Engineering cell and growth in MC3T3-E1 osteoblasts via an ERK 1/2shape and function. Science 1994; 264: 696698. pathway. J Bone Miner Res 2003; 18: 5866.
34. Dike L, Chen CS, Mrkisch M, Tien J, Whitesides GM, 55. Berry CC, Cacou C, Lee DA, Bader DL, Shelton JC.Ingber DE. Geometric control of switching between growth, Dermal broblasts respond to mechanical conditioning in aapoptosis,and differentiation during angiogenesis using strain prole dependent manner. Biorheology 2003; 40: 337micropatterned substrates. In Vitro Cell Dev Biol 1999; 35: 45.441448. 56. Miller CE, Donlon KJ, Toia L, Wong CL, Chess PR. Cyclic
35. Chen CS, Mrksich M, Huang S, Whitesides G, Ingber DE. strain induces proliferation of cultured embryonic heart cells.Geometric control of cell life and death. Science 1997; 276: In Vitro Cell Dev Biol Anim 2000; 36: 6339.14258. 57. Matsuda N, Yokoyama K, Takeshita S, Watanabe M. Role
36. Lo CM, Wang HB, Dembo M, Wang YL. Cell movement is of epidermal growth factor and its receptor in mechanicalguided by the rigidity of the substrate. Biophys J 2000; 79: stress-induced differentiation of human periodontal ligament14452. cells in vitro. Arch Oral Biol 1998; 43: 98797.
37. Parker KK, Brock AL, Brangwynne C, Mannix RJ, Wang 58. Davies PF. Flow-mediated endothelial mechanotransduc-N, Ostuni E, et al. Directional control of lamellipodia tion. Physiol Rev 1995; 75: 51960.extension by constraining cell shape and orienting cell
59. Resnick N, Yahav H, Khachigian LM, Collins T, Ander-tractional forces. FASEB J 2002; 16: 1195204.
son KR, Dewey FC, et al. Endothelial gene regulation by38. Korff T, Augustin HG. Tensional forces in brillarlaminar shear stress. Adv Exp Med Biol 1997; 430: 15564.
extracellular matrices control directional capillary sprouting.60. Praetorius HA, Spring KR. Bending the MDCK cell primary
J Cell Sci 1999; 112: 324958.cilium increases intracellular calcium. J Membr Biol 2001;
39. Bray D. Axonal growth in response to experimentally184: 719.
applied mechanical tension. Dev Biol 1984; 102: 37989.61. Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li
40. Lee K-M, Tsai K, Wang N, Ingber DE. Extracellular matrixX, et al. Polycystins 1 and 2 mediate mechanosensation in the
and pulmonary hypertension: control of vascular smoothprimary cilium of kidney cells. NatGenet2003; 33: 12937.
muscle cell contractility. Am J Physiol 1998; 274: H7682.62. Park JM, Yang T, Arend LJ, Schnermann JB, Peters CA,
41. Tan JL, Tien J, Pirone DM, Gray DS, Bhadriraju K, ChenFreeman MR, et al. Obstruction stimulates COX-2 expres-
CS. Cells lying on a bed of microneedles: an approach tosion in bladder smooth muscle cells via increased mechanical
isolate mechanical force. Proc Natl Acad Sci USA 2003; 100:stretch. Am J Physiol 1999; 276: F12936.
14849.63. Ichikawa I. Direct analysis of the effector mechanism of the
42. Huang S, Ingber DE. The structural and mechanicaltubuloglomerular feedback system. Am J Physiol 1982; 243:
complexity of cell growth control. NatCell Biol 1999; 1:F44755.
E1318. 64. Oldenhof AD, Shynlova OP, Liu M, Langille BL, Lye SJ.43. Moore KA, Huang S, Kong Y, Sunday ME, Ingber DE.
Mitogen-activated protein kinases mediate stretch-induced c-Control of embryonic lung branching morphogenesis by the
fos mRNA expression in myometrial smooth muscle cells.Rho activator,cytotoxic necrotizing factor 1. J Surg ResAm J Physiol Cell Physiol 2002; 283: C15309.2002; 104: 95100.
65. Wirtz HR, Dobbs LG. Calcium mobilization and exocytosis44. Ingber DE. Mechanical Signaling and the Cellular Responseafter one mechanical stretch of lung epithelial cells. Scienceto Extracellular Matrix in Angiogenesis and Cardiovascular1990; 250: 12669.Physiology. Circ Res 2002; 91: 87787.
66. Chen J, Fabry B, Schiffrin EL, Wang N. Twisting integrin45. Galli-Resta L. Putting neurons in the right places: localreceptors increases endothelin-1 gene expression in endothe-interactions in the genesis of retinal architecture. Trendslial cells. Am J Physiol Cell Physiol 2001; 280: C147584.Neurosci 2002; 25: 63843.
67. Stamenovic D, Liang Z, Chen J, Wang N. Effect of the46. Van Essen DC. A tension-based theory of morphogenesiscytoskeletal prestress on the mechanical impedance ofand compact wiring in the central nervous system. Naturecultured airway smooth muscle cells. J Appl Physiol 2002;1997; 385: 3138.92: 144350.47. Duncan RL. Transduction of mechanical strain in bone.
68. Choquet D, Felsenfeld DP, Sheetz MP. Extracellular matrixASGSB Bull 1995; 8: 4962.rigidity causes strengthening of integrin-cytoskeleton link-48. Carter DR, Orr TE, Fyhrie DP, Schurman DJ. Inuences ofages. Cell 1997; 88: 3948.mechanical stress on prenatal and postnatal skeletal devel-
69. Balaban NQ, Schwarz US, Riveline D, Goichberg P, Tzuropment. Clin Orthop 1987; 219: 23750.G, Sabanay I, et al. Force and focal adhesion assembly: a49. Grodzinsky AJ, Levenston ME, Jin M, Frank EH.close relationship studied using elastic micropatternedCartilage tissue remodeling in response to mechanical forces.substrates. NatCell Biol 2001; 3: 46672.Annu Rev Biomed Eng 2000; 2: 691713.
70. Riveline D, Zamir E, Balaban NQ, Schwarz US, Ishizaki50. Hatfaludy S, Shansky J, Vandenburgh HH. Metabolic
T, Narumiya S, et al. Focal contacts as mechanosensors:alterations induced in cultured skeletal muscle by stretch-
externally applied local mechanical force induces growth ofrelaxation activity. Am J Physiol 1989; 256: C17581.focal contacts by an mDia1-dependent and ROCK-indepen-51. Vandenburgh HH, Swasdison S, Karlisch P. Computer-dent mechanism. J Cell Biol 2001; 153: 117586.aided mechanogenesis of skeletal muscle organs from single
cells in vitro. FASEB J 1991; 5: 28607. 71. Maniotis A, Chen C, Ingber DE. Demonstration of mech-
52. Kim SH, Koh GY, Cho KW, Park WY, Seo JS. Stretch- anical connections between integrins,cytoskeletal laments
# 2003 Taylor & Francis. ISSN 0785-3890 Annals of Medicine 35
T&F -:- FULL SGML TEXT -:- Annals of Medicine MS. 149 Op. PGW {F2-PDF}
N:/SANN/149/149.3D Produced: 24/07/2003 At: 14:39:26
Page Count:14 Page Range:114 Page:11
-
7/29/2019 Mechano Biology
11/14
12 I
NGBER
and nucleoplasm that stabilize nuclear structure. Proc Natl 91. Goldschmidt ME, McLeod KJ, Taylor WR. Integrin-
Acad Sci USA 1997; 94: 84954. mediated mechanotransduction in vascular smooth muscle
72. Wang N, Naruse K, Stamenovic D, Fredberg J, Mijai lovic cells: frequency and force response characterist ics. Circ Res
SM, Maksym G, Polte T, Ingber DE. Mechanical behavior 2001; 88: 67480.
in living cells consistent with the tensegrity model. Proc Natl 92. Sachs F, Sokabe M. Stretch-activated ion channels andAcad Sci USA 2001; 98: 776570. membrane mechanics. Neurosci Res Suppl 1990; 12: S14.
73. Helmke BP, Goldman RD, Davies PF. Rapid displacement 93. Hamill OP, Martinac B. Molecular basis of mechanotrans-of vimentin intermediate laments in living endothelial cells duction in living cells. Physiol Rev 2001; 81: 685740.exposed to ow. Circ Res 2000; 86: 74552. 94. Garcia-Anoveros J, Corey DP. The molecules of mechan-
74. Ingber DE, Tensegrity II. How structural networks inu- osensation. Annu Rev Neurosci 1997; 20: 56794.
ence cellular information processing networks. J Cell Sci 95. Day BL, Cole J. Vestibular-evoked postural responses in the2003; 116: 1397408. absence of somatosensory information. Brain 2002; 125:
75. Ingber DE. The riddle of morphogenesis: a question of 20818.solution chemistry or molecular cell engineering? Cell 1993; 96. Garcia-Anoveros J, Samad TA, Zuvela-Jelaska L, Woolf75: 124952. CJ, Corey DP. Transport and localization of the DEG/ENaC
76. Janmey PA. The cytoskeleton and cell signaling: component ion channel BNaC1alpha to peripheral mechanosensorylocalization and mechanical coupling. Physiol Rev 1998; 78: terminals of dorsal root ganglia neurons. J Neurosci 2001;76381. 21: 267886.
77. Plopper GE, McNamee HP, Dike LE, Bojanowski K, 97. Price MP, McIlwrath SL, Xie J, Cheng C, Qiao J, Tarr DE,Ingber DE. Convergence of integrin and growth factor et al. The DRASIC cation channel contributes to thereceptor signaling pathways within the focal adhesion detection of cutaneous touch and acid stimuli in mice.complex. Mol Biol Cell 1995; 6: 134965. Neuron 2001; 32: 107183.
78. Miyamoto S, Teramoto H, Coso OA, Gutkind JS, Burbelo 98. Alenghat FJ, Ingber DE. Mechanotransduction: all signalsPD, Akiyama SK, et al. Integrin function: molecular
point to cytoskeleton,matrix,and integrins. Sci STKEhierarchies of cytoskeletal and signaling molecules. J Cell
(www.stke.org/cgi/content/full/OC_sigtrans;2002/119/Biol 1995; 131: 791805.pe5).
79. Galbraith CG, Yamada KM, Sheetz MP. The relationship99. Davis MJ, Wu X, Nurkiewicz TR, Kawasaki J, Davis GE,
between force and focal complex development. J Cell BiolHill MA, et al. Integrins and mechanotransduction of the
2002; 159: 695705.vascular myogenic response. Am J Physiol HeartCirc Physiol
80. Chen BM, Grinnell AD. Kinetics,Ca2+ dependence,and2001; 280: H142733.
biophysical properties of integrin-mediated mechanical100. Huang S, Chen CS, Ingber DE. Control of cyclin D1,
modulation of transmitter release from frog motor nervep27 and cell cycle progression in human capillaryKi p1
terminals. J Neurosci 1997; 17: 90416.endothelial cells by cell shape and cytoskeletal tension. Mol
81. Chicurel ME, Singer RH, Meyer C, Ingber DE. IntegrinBiol Cell 1998; 9: 317993.
binding and mechanical tension induce movement of mRNA101. Flusberg DA, Numaguchi Y, Ingber DE. Cooperative
and ribosomes to focal adhesions. Nature 1998; 392: 7303.control of Akt phosphorylation and apoptosis by cytoskeletal
82. Meyer CJ, Alenghat FJ, Rim P, Fong JH-J, Fabry B, Ingbermicrolaments and microtubules. Mol Biol Cell 2001; 12:
DE. Mechanical control of cyclic AMP signaling and gene308794.
transcription through integrins. NatCell Biol 2000; 2: 6668.102. Gebb SA, Graham JA, Hanger CC, Godbey PS, Capen RL,
83. Tang D, Mehta D, Gunst SJ. Mechanosensitive tyrosine Doerschuk CM, et al. Sites of leukocyte sequestration in thephosphorylation of paxillin and focal adhesion kinase in
pulmonary microcirculation. J Appl Physiol 1995; 79: 4937.tracheal smooth muscle. Am J Physiol 1999; 276: C2508.
103. Saito H, Lai J, Rogers R, Doerschuk CM. Mechanical84. Lee HS, Millward-Sadler SJ, Wright MO, Nuki G, Salterproperties of rat bone marrow and circulating neutrophilsDM. Integrin and mechanosensitive ion channel-dependentand their responses to inammatory mediators. Blood 2002;tyrosine phosphorylation of focal adhesion proteins and99: 220713.beta-catenin in human articular chondrocytes after mechani-
104. Weiss L, Elkin G, Barbera-Guillem E. The differentialcal stimulation. J Bone Miner Res 2000; 15: 15019.resistance of B16 wild-type and F10 cells to mechanical85. Chen KD, Li YS, Kim M, Li S, Yuan S, Chien S, Shyy JY.trauma in vitro. Invasion Metastasis 1993; 13: 92101.Mechanotransduction in response to shear stress. Roles of
105. Melder RJ, Kristensen CA, Munn LL, Jain RK. Modula-receptor tyrosine kinases,integrins,and Shc. J Biol Chemtion of A-NK cell rigidity: In vitro characterization and in1999; 274: 18393400.vivo implications for cell delivery. Biorheology 2001; 38:86. Liu Y, Chen BP, Lu M, Zhu Y, Stemerman MB, Chien S, et1519.al. Shear stress activation of SREBP1 in endothelial cells is
106. Cortes P, Riser BL, Yee J, Narins RG. Mechanical strain ofmediated by integrins. Arterioscler Thromb Vasc Biol 2002;
glomerular mesangial cells in the pathogenesis of glomerulo-22: 7681.sclerosis: clinical implications. Nephrol Dial Transplant87. Franchini KG, Torsoni AS, Soares PH, Saad MJ. Early1999; 14: 13514.activation of the multicomponent signaling complex asso-
107. Kagami S, Kondo S, Urushihara M, Loster K, Reutter W,ciated with focal adhesion kinase induced by pressureSaijo T, et al. Overexpression of alpha1beta1 integrinoverload in the rat heart. Circ Res 2000; 87: 55865.directly affects rat mesangial cell behavior. Kidney Int88. Williams B. Mechanical inuences on vascular smooth2000; 58: 108897.muscle cell function. J Hypertens 1998; 6: 19219.
108. Waters CM, Sporn PH, Liu M, Fredberg JJ. Cellular89. Katsumi A, Milanini J, Kiosses WB, del Pozo MA, Kaunas
biomechanics in the lung. Am J Physiol Lung Cell MolR, Chien S, et al. Effects of cell tension on the small GTPase
Physiol 2002; 283: L5039.Rac. J Cell Biol 2002; 158: 15364.109. Redowicz MJ. Myosins and pathology: genetics and90. Putnam AJ, Cunningham JJ, Pillemer BB, Mooney DJ.
biology. Acta Biochim Pol 2002; 49: 789804.External mechanical strain regulates membrane targeting of
Rho GTPases by controlling microtubule assembly. Am J 110. Lynch ED, Lee MK, Morrow JE, Welcsh PL, Leon PE,
Physiol Cell Physiol 2003; 284: C62739. King MC. Nonsyndromic deafness DFNA1 associated with
# 2003 Taylor & Francis. ISSN 0785-3890 Annals of Medicine 35
T&F -:- FULL SGML TEXT -:- Annals of Medicine MS. 149 Op. PGW {F2-PDF}
N:/SANN/149/149.3D Produced: 24/07/2003 At: 14:39:26
Page Count:14 Page Range:114 Page:12
-
7/29/2019 Mechano Biology
12/14
D 13ISEASES OF MECHANOTRANSDUCTION
mutation of a human homolog of the Drosophila gene mouse model of congenital muscular dystrophy. Mol Genet
diaphanous. Science 1997; 278: 13158. Metab 2002; 76: 21724.
111. Zheng L, Sekerkova G, Vranich K, Tilney LG, Mugnaini 131. Szymko-Bennett YM, Kurima K, Olsen B, Seegmiller R,
E, Bartles JR. The deaf jerker mouse has a mutation in the Grifth AJ. Auditory function associated with Col11a1
gene encoding the espin actin-bundling proteins of hair cell haploinsufciency in chondrodysplasia (cho) mice. Hear Resstereocilia and lacks espins. Cell 2000; 102: 37785. 2003; 175: 17882.
112. Boulassel MR, Deggouj N, Tomasi JP, Gersdorff M. Inner 132. Westaby S. Aortic dissection in Marfan's syndrome. Annear autoantibodies and their targets in patients with Thorac Surg 1999; 67: 18613.autoimmune inner ear diseases. Acta Otolaryngol 2001; 133. Peacock DJ, Banquerigo ML, Brahn E. Angiogenesis121: 2834. inhibition suppresses collagen arthritis. J Exp Med 1992;
113. Littlewood Evans A, Muller U. Stereocilia defects in the 175: 11358.sensory hair cells of the inner ear in mice decient in integrin 134. Ingber DE, Madri JA, Jamieson JD. Role of basal lamina inalpha8beta1. NatGenet2000; 24: 4248. the neoplastic disorganization of tissue architecture. Proc
114. Tomasek J, Rayan GM. Correlation of alpha-smooth Natl Acad Sci USA 1981; 78: 39015.muscle actin expression and contraction in Dupuytren's 135. Ingber DE. Cancer as a disease of epithelia-mesenchymaldisease broblasts. J Hand Surg [Am] 1995; 20: 4505. interactions and extracellular matrix regulation. Differentia-
115. Wiederholt M, Thieme H, Stumpff F. The regulation of tion 2002; 70: 54760.trabecular meshwork and ciliary muscle contractility. Prog 136. Sternlicht MD, Bissell MJ, Werb Z. The matrix metallo-Retin Eye Res 2000; 19: 27195. proteinase stromelysin-1 acts as a natural mammary tumor
116. Pena A, Bolton MD, Whitehouse H, Pickard JD. Effects of promoter. Oncogene 2000; 19: 110213.brain ventricular shape on periventricular biomechanics: a 137. Sternlicht MD, Lochter A, Sympson CJ, Huey B, Rougiernite-element analysis. Neurosurgery 1999; 45: 10716. JP, Gray JW, et al. The stromal proteinase MMP3/
117. Waitkus-Edwards KR, Martinez-Lemus LA, Wu X, stromelysin-1 promotes mammary carcinogenesis. CellTrzeciakowski JP, Davis MJ, Davis GE, et al. alpha(4)
1999; 98: 13746.beta(1) Integrin activation of L-type calcium channels in
138. Folkman J, Watson K, Ingber DE, Hanahan D. Inductionvascular smooth muscle causes arteriole vasoconstriction.of angiogenesis during the transition from hyperplasia to
Circ Res 2002; 90: 47380.neoplasia. Nature 1989; 339: 5861.
118. Jalali S, del Pozo MA, Chen K, Miao H, Li Y, Schwartz139. Fang J, Shing Y, Wiederschain D, Yan L, Buttereld C,
MA, et al. Integrin-mediated mechanotransduction requiresJackson G, et al. Matrix metalloproteinase-2 is required for
its dynamic interaction with specic extracellular matrixthe switch to the angiogenic phenotype in a tumor model.
(ECM) ligands. Proc Natl Acad Sci USA 2001; 98: 10426.Proc Natl Acad Sci USA 2000; 97: 38849.
119. Balogh J, Merisckay M, Li Z, Paulin D, Arner A. Hearts140. Bode F, Sachs F, Franz MR. Tarantula peptide inhibits
from mice lacking desmin have a myopathy with impairedatrial brillation. Nature 2001; 409: 356.
active force generation and unaltered wall compliance.141. Spence HJ, Chen YJ, Winder SJ. Muscular dystrophies,the
Cardiovasc Res 2002; 53: 43950.cytoskeleton and cell adhesion. Bioessays 2002; 24: 54252.
120. Loufrani L, Matrougui K, Li Z, Levy BI, Lacolley P, Paulin142. Burkin DJ, Wallace GQ, Nicol KJ, Kaufman DJ, Kaufman
D, et al. Selective microvascular dysfunction in mice lackingSJ. Enhanced expression of the alpha 7 beta 1 integrin
the gene encoding for desmin. FASEB J 2002; 16: 1179.reduces muscular dystrophy and restores viability in dys-
121. Keller RS, Shai SY, Babbitt CJ, Pham CG, Solaro RJ,trophic mice. J Cell Biol 2001; 152: 120718.
Valencik ML, et al. Disruption of integrin function in the 143. Gillis JM. Understanding dystrophinopathies: an inventorymurine myocardium leads to perinatal lethality,brosis,and
of the structural and functional consequences of the absenceabnormal cardiac performance. Am J Pathol 2001; 158: 1079
of dystrophin in muscles of the mdx mouse. J Muscle Res90.Cell Motil 1999; 20: 60525.122. Hunter JJ, Chien KR. Signaling pathways for cardiac
144. Goldspink G. Changes in muscle mass and phenotype andhypertrophy and failure. N Engl J Med 1999; 341: 127683.the expression of autocrine and systemic growth factors by123. Iglesias X, Espuna M, Puig M, Davi E, Ribas C, Palau MJ.muscle in response to stretch and overload. J Anat 1999; 194:Pubic bone anchoring devices for the surgical treatment of32334.urinary stress incontinence in patients with severe genital
145. Pasternak C, Wong S, Elson EL. Mechanical function ofprolapse. IntUrogynecol J Pelvic Floor Dysfunct2002; 13:dystrophin in muscle cells. J Cell Biol 1995; 128: 35561.3148.
146. Carmeliet G, Vico L, Bouillon R. Space ight: a challenge124. Italiano G, Calabro A, Spini S, Ragazzi E, Pagano F.for normal bone homeostasis. CritRev EukaryotGene ExprFunctional response of cavernosal tissue to distension. Urol2001; 11: 13144.Res 1998; 26: 3944.
147. Anderson HC. An antagonist of osteoclast integrins125. Levin RJ. The physiology of sexual arousal in the human
prevents experimental osteoporosis. J Clin Invest 1997; 99:female: a recreational and procreational synthesis. Arch Sex2059.Behav 2002; 31: 40511.
148. Loth F, Fischer PF, Arslan N, Bertram CD, Lee SE,126. Levin SM. The tensegrity-truss as a model for spineRoyston TJ, et al. Transitional ow at the venousmechanics. J Mechan Med Bio 2002; 2: 37588.anastomosis of an arteriovenous graft: potential activation127. Masi AT, Walsh EG. Ankylosing spondylitis: integratedof the ERK1/2 mechanotransduction pathway. J Biomechclinical and physiological perspectives. Clin Exper RheumEng 2003; 125: 4961.2003; 21: 18.
149. Uhlig S. Ventilation-induced lung injury and mechanotrans-128. Olsen BR. Mutations in collagen genes resulting in
duction: stretching it too far? Am J Physiol Lung Cell Molmetaphyseal and epiphyseal dysplasias. Bone 1995; 17: 45S9.
Physiol 2002; 282: L8926.129. Spranger J. Changes in clinical practice with the unravelling150. Avery ME, Taeusch HW, Floros J. Surfactant replacement.of diseases: connective-tissue disorders. J InheritMetab Dis
N Engl J Med 1986; 315: 8256.2001; 24: 11726.
130. Pil lers DA, Kempton JB, Duncan NM, Pang J, Dwinnell 151. The Acute Respiratory Distress Syndrome Network. Venti-
SJ, Trune DR. Hearing loss in the laminin-decient dy lation with lower tidal volumes as compared with traditional
# 2003 Taylor & Francis. ISSN 0785-3890 Annals of Medicine 35
T&F -:- FULL SGML TEXT -:- Annals of Medicine MS. 149 Op. PGW {F2-PDF}
N:/SANN/149/149.3D Produced: 24/07/2003 At: 14:39:27
Page Count:14 Page Range:114 Page:13
-
7/29/2019 Mechano Biology
13/14
14 I
NGBER
tidal volumes for acute lung injury and the acute respiratory 162. Udagawa T, Yuan J, Panigrahy D, Chang YH, Shah J,
distress syndrome. N Engl J Med 2000; 342: 13018. D'Amato RJ, Cytochalasin E. an epoxide containing
152. Edelman ER, Rogers C. Pathobiologic responses to stenting. Aspergillus-derived fungal metaboli te,inhibits angiogenesis
Am J Cardiol 1998; 81: 4E6. and tumor growth. J Pharmacol Exp Ther 2000; 294: 4217.153. Takei T, Mills I, Arai K, Sumpio BE. Molecular basis for 163. Brooks PC, Clark RA, Cheresh DA. Requirement of
tissue expansion: clinical implications for the surgeon. Plast vascular integrin alpha v beta 3 for angiogenesis. ScienceReconstr Surg 1998; 102: 24758. 1994; 264: 56971.
154. Webb LX. New techniques in wound management: vacuum- 164. Ingber DE, Madri JA, Folkman J. A. possible mechanismassisted wound closure. J Am Acad Orthop Surg 2002; 10: for inhibition of angiogenesis by angiostatic steroids:30311. induction of capillary basement membrane dissolution.
155. Langevin HM, Churchill DL, Cipolla MJ. Mechanical Endocrinology 1986; 119: 176875.signaling through connective tissue: a mechanism for the
165. Ingber DE, Folkman J. Inhibition of angiogenesis throughtherapeutic effect of acupuncture. FASEB J 2001; 15: 2275
inhibition of collagen metabolism. Lab Invest 1988; 59: 4482.
51.156. McNeil DG Jr. Wrinkles Gone? New Uses Studied for
166. Moses MA, Langer R. Metalloproteinase inhibition as aBotox. New York Times. March 2,2003.
mechanism for the inhibition of angiogenesis. EXS 1992; 61:157. Waki M, Yoshida Y, Oka T, Azuma M. Reduction of
14651.intraocular pressure by topical administration of an inhibitor
167. Vandenburgh HH, Solerssi R, Shansky J, Adams JW,of the Rho-associated protein kinase. Curr Eye Res 2001; 22:
Henderson SA. Mechanical stimulation of organogenic4704.
cardiomyocyte growth in vitro. Am J Physiol 1996; 270:158. Sawada N, Itoh H, Ueyama K, Yamashita J, Doi K, Chun
C128492.TH, et al. Inhibition of rho-associated kinase results in
168. Weston MW, Yoganathan AP. Biosynthetic activity in heartsuppression of neointimal formation of balloon-injured
valve leaets in response to in vitro ow environments. Annarteries. Circulation 2000; 101: 20303.
Biomed Eng 2001; 29: 75263.159. Masumoto A, Hirooka Y, Shimokawa H, Hironaga K,169. Powell CA, Smiley BL, Mills J, Vandenburgh HH.Setoguchi S, Takeshita A. Possible involvement of Rho-
Mechanical stimulation improves tissue-engineered humankinase in the pathogenesis of hypertension in humans.skeletal muscle. Am J Physiol Cell Physiol 2002; 283: C1557Hypertension 2001; 38: 130710.65.160. Shimokawa H, Hiramori K, Iinuma H, Hosoda S, Kishida
170. Kodis T, Akhyari P, Boublik J, Theodorou P, Martin U,H, Osada H, et al. Anti-anginal effect of fasudil,a Rho-Ruhparwar A, et al. In vitro engineering of heart muscle:kinase inhibitor,in patients with stable effort angina: aarticial myocardial tissue. J Thorac Cardiovasc Surg 2002;multicenter study. J Cardiovasc Pharmacol 2002; 40: 75161.124: 639.161. D'Amato RJ, Lin CM, Flynn E, Folkman J, Hamel E. 2-
171. Niklason LE, Gao J, Abbott WM, Hirschi KK, Houser S,Methoxyestradiol,an endogenous mammalian metabolite,Marini R, et al. Functional arteries grown in vitro. Scienceinhibits tubulin polymerization by interacting at the colchi-1999; 284: 48993.cine site. Proc Natl Acad Sci USA 1994; 91: 39648.
# 2003 Taylor & Francis. ISSN 0785-3890 Annals of Medicine 35
T&F -:- FULL SGML TEXT -:- Annals of Medicine MS. 149 Op. PGW {F2-PDF}
N:/SANN/149/149.3D Produced: 24/07/2003 At: 14:39:28
Page Count:14 Page Range:114 Page:14
-
7/29/2019 Mechano Biology
14/14