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Martin Schwartz, PhD

Robert W. Berliner Professor of Medicine (Cardiology) and Professor of Biomedical Engineering and of Cell Biology

Research Summary

Our work aims to understand how cells and tissues respond to mechanical forces. These studies span dimensional scales from single molecules to cells to tissues and animal models. They include basic science projects to understand fundamental mechanisms of mechanotransduction through cell adhesion receptors such as integrins and PECAM1, utilizing a variety of biophysical and cellular tools to understand how cells sense both externally applied stress and the mechanical features of their environment. Discoveries at the molecular scale are then exploited to understand how blood vessels sense mechanical forces from blood flow (fluid shear stress) and blood pressure (wall stress) and how cell responses to these forces determines vascular physiology and remodeling and disease. Lastly, we are applying results from these molecular/cellular studies to understand vascular remodeling and diseases that are characterized by pathological remodeling such as atherosclerosis, vascular malformations and aneurysms.

Extensive Research Description

Overview and Philosophy

Regulation of cell behavior by adhesion to extracellular matrix (ECM) and mechanical forces are fundamental facts of multicellular life. Cell adhesion to ECM critically regulates cell survival, growth, gene expression and function. Integrins are the major membrane receptors that mediate adhesion of cells to ECM; they also connect the actin cytoskeleton inside the cell to the ECM to provide mechanical integrity, and transmit signals that depend on the composition, organization and mechanical properties of the matrix. Similarly, mechanical forces are fundamental to life, serving as critical guides for morphogenesis and repair.Mechanical forces are especially critical in the cardiovascular system, whose primary function is pumping and delivery of blood to the tissues. Mechanical forces from blood flow, both fluid shear stress, the frictional force from blood flow, and wall stress from blood pressure, are critical for the development, maintenance, physiology and major diseases of the vascular system.

My lab has built an integrated, multi-disciplinary program that combines biophysical, cellular and whole animal approaches to study these problems.We aim to unravel fundamental mechanisms of mechanotransduction through integrins and shear stress receptors, to elucidate the cellular signaling networks that mediate effects on cell behavior and gene expression, and animal models to understand how these events play out during development, in normal physiology, and in vascular diseases such as atherosclerosis.

My laboratory has therefore developed an integrated program addressing interesting problems in cell adhesion, signaling and mechanotransduction.We are currently working in 4 major areas.

Mechanotransduction by integrins

Cells sense the mechanical properties of their ECM and respond accordingly [1].They also respond to external forces applied through the ECM [2].Exhaustive evidence has shown that integrins mediate these responses but the molecular mechanisms are not well understood. We are currently investigating the role of integrin conformation and the cytoskeletal adapter talin in these processes. We have developed a panel of integrin and talin mutants with specific alterations in conformation or mechanical variables, and are studying how these alter cellular responses to matrix stiffness and stretch.

Additionally, we developed a fluorescence-based method to measure forces across specific proteins in live cells [3]. Studies using this approach with the focal adhesion protein talin, which connects integrins to the actin cytoskeleton, showed that this protein bears force and that it plays a role in how cells sense matrix stiffness [4]. We are currently combining this sensor with high resolution microscopy and speckle imaging of actin dynamics to elucidate how integrin-mediated adhesions respond to force at the near-single molecule level, in order to elucidate these molecular mechanisms.

Fluid shear stress mechanotransduction in the vascular system

Flowing blood exerts a frictional force called fluid shear stress on the endothelial cells that line the vessels; this force is a major determinant of vascular development, physiology and disease [5]. Atherosclerosis arises in regions of arteries subject to disturbances in fluid flow patterns, while high fluid shear stress suppresses inflammatory and atherosclerotic pathways.We have identified complex between VE-cadherin, PECAM-1 and VEGFR2 as a critical mechanotransducer that mediates a subset of these effects [6]. Continuing studies on the junctional complex elucidated mechanisms of force transmission [7] and key architectural features [8]. Our continuing studies in mice are investigating how these molecular processes determine physiological vascular remodeling and development of atherosclerosis.

One major pathway downstream of the junctional complex involves activation of integrins, binding to the subendothelial extracellular matrix and subsequent signaling.An important consequence of this pathway is that cell responses to flow are modulated by the ECM. We have found that basement membrane proteins promote flow-dependent activation of anti-inflammatory pathways; by contrast, endothelial cells on provisional ECM proteins such as fibronectin activate multiple inflammatory pathways [9-11].Further studies identified a mechanism by which fibronectin promotes inflammatory activation of the endothelium by binding and activating the cAMP-specific phosphodiesterase 4D5 [12]. This results in decreased signaling through the anti-inflammatory cAMP/protein kinase a pathway, thus creating a cellular state that is permissive for activation by inflammatory mediators. We are continuing to investigate more deeply the molecular mechanisms that mediate these events and understand their consequences in animal models of vascular remodeling and disease.

Collateral artery formation

Blockage of a coronary artery after myocardial infarction leads to downstream ischemia and myocardial cell death. A major mechanism of resistance and recovery is that blockage of an artery triggers increased flow through parallel vessels, which then remodel to accommodate the higher flow. In human patients, this ability to form collateral arteries that perfuse the affected region is a major determinant of recovery after MI.However, the key steps by which high flow stimulates arterialization of small vessels are not well understood, nor are the reasons why some patients are unable to do so.We are currently applying our expertise in flow signaling to address this medical problem.Our first study of the basic pathway of flow-dependent vessel remodeling demonstrated that endothelial cells encode a fluid shear stress set point, such that shear stress above or below that level triggered outward or inward remodeling [13].Further, we found that the value for the set point was determined in part by signaling through the junctional complex. We are continuing to study the mechanisms that determine the set point and to then identify the steps that are inhibited in poor responders in order to devise therapies to improve outcomes.


Healthy arteries remodel to resist the applied forces forces from blood pressure, to become thicker or thinner when blood pressure increases or decreases, respectively. Aneurysms represent a form of pathological remodeling where the artery wall expands thins and weakens under too-high pressure, eventually resulting in rupture or separation of the layers of the vessel wall, events that are often fatal. Aneurysms may be caused by very high blood pressure in normal people or normal blood pressure in people that carry mutations in genes that mediate mechanosensing or mechanical strength [14]. We aim to understand the fundamental mechanisms by which cells of the artery wall sense wall stress to regulate physiological remodeling, and what goes wrong in aneurysms.


1. Grashoff, C., et al., Measuring mechanical tension across vinculin reveals regulation of focal adhesion dynamics. Nature, 2010. 466(7303): p. 263-6.

2. Kumar, A., et al., Talin tension sensor measurements reveal novel features of focal adhesion force transmission and mechanosensitivity. J. Cell Biol., 2016. in press.

5. Hahn, C. and M.A. Schwartz, Mechanotransduction in vascular physiology and atherogenesis. Nat Rev Mol Cell Biol, 2009. 10(1): p. 53-62.

6.Tzima, E., et al., Identification of a mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature, 2005. 437: p. 426-431.

7.Conway, D.E., et al., Fluid shear stress on endothelial cells modulates mechanical tension across VE-cadherin and PECAM-1. Curr Biol, 2013. 23(11): p. 1024-30.

8.Coon, B.G., et al., Intramembrane binding of VE-cadherin to VEGFR2 and VEGFR3 assembles the endothelial mechanosensory complex. J Cell Biol, 2015.

9. Yun, S., et al., Interaction between integrin alpha5 and PDE4D regulates endothelial inflammatory signalling. Nat Cell Biol, 2016. 18(10): p. 1043-53.

10. Baeyens, N., et al., Vascular remodeling is governed by a VEGFR3-dependent fluid shear stress set point. Elife, 2015. 4.

11. Humphrey J. et al, Dysfunctional mechanosensing in aneurysms. Science. 2014 344(6183):477-9.

12. Baeyens N., et al. Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia. J. Cell Biol. 2016, 214:807-16.

13. Conway D. et al VE-Cadherin Phosphorylation Regulates Endothelial Fluid Shear Stress Responses through the Polarity Protein LGN. Curr Biol 2017 27(14):2219-2225.

14. Kumar A. et al, Filamin A mediates isotropic distribution of applied force across the actin network. J Cell Biol. 2019 218(8):2481-2491.

15. Yun S. et al, Integrin α5β1 regulates PP2A complex assembly through PDE4D to control atherosclerosis. J Clin Invest. 2019, 130:4863-4874.


Research Interests

Aneurysm; Cell Biology; Atherosclerosis; Vascular Malformations; Vascular Remodeling

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Selected Publications