Our current work is in two areas. First, we have a basic science project to understand fundamental mechanisms of mechanotransduction through integrins. These studies utilize a variety of biophysical and cellular tools to understand how cells sense both externally applied stress and matrix stiffness through integrin-mediated adhesions. Second, we are working to understand how vascular endothelial cells sense fluid shear stress from blood flow and how it determines vascular physiology and disease. This project encompasses biophysical approaches to address fundamental molecular mechanisms, cellular approaches to elucidate signaling pathways, and animal studies to work out consequences for vascular remodeling and development of atherosclerosis.
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 .They also respond to external forces applied through the ECM .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 in these processes. We have developed a panel of integrin mutants with specific alterations in conformation, 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 . 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 . 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 . 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 . Continuing studies on the junctional complex elucidated mechanisms of force transmission  and key architectural features . 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 . 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 .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.
- Conway DE, Breckenridge MT, Hinde E, Gratton E, Chen CS, Schwartz MA. Fluid Shear Stress on Endothelial Cells Modulates Mechanical Tension across VE-Cadherin and PECAM-1. Curr Biol. 2013 Jun 3, 23:1024-30
- Hoffman, B.D., Grashoff, C. and Schwartz, M.A. Dynamic molecular processes mediate cellular mechanotransduction. Nature. 2011, 475:316-323.
- Grashoff C., Hoffman BD., Brenner MD., Zhou R., Parsons M., Yang MT., McLean MA., Sligar SG., Chen CS., Ha T. and Schwartz, MA.. Measuring mechanical tension across vinculin reveals regulation of focal adhesion dynamics. Nature, 2010,466:263-6.
- Orr, A.W., Stockton, R., Simmers,M.B., Sanders, J.M., Sarembock, I.J., Blackman, B.R., Schwartz, M.A. Matrix-specific p21-activated kinase activation regulates vascular permeability in atherogenesis. J Cell Biol. 2007, 176:719-727.
- Balasubramanian, N., Scott, D.W., Castle, J.D., Casanova, J.E., Schwartz, M.A. Arf6 and microtubules in adhesion-dependent trafficking of lipid rafts. Nat Cell Biol. 2007, 9:1381-1391.
- Tzima, E, Irani-Tehrani, M., Kiosses, W. B., Dejana, E., Schultz, D. A., Engelhardt, B., Cao, G., DeLisser, H., Schwartz, M. A. Identification of a mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 2005, 437:426-430.
Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia.
J Cell Biol. 26;214(7):807-16.
Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling.
Nat Cell Biol. ;18(10):1043-53
An Osteopontin/CD44 Axis in RhoGDI2-Mediated Metastasis Suppression.
Cancer Cell. 30(3):432-43
Talin tension sensor reveals novel features of focal adhesion force transmission and mechanosensitivity.
J Cell Biol. 213(3):371-83
Endothelial fluid shear stress sensing in vascular health and disease.
J Clin Invest. 126(3):821-8
Full List of PubMed Publications
- Wang Y, Baeyens N, Corti F, Tanaka K, Fang JS, Zhang J, Jin Y, Coon B, Hirschi KK, Schwartz MA, Simons M: Syndecan 4 controls lymphatic vasculature remodeling during mouse embryonic development. Development. 2016 Dec 1; 2016 Oct 27. PMID: 27789626
- Yun S, Budatha M, Dahlman JE, Coon BG, Cameron RT, Langer R, Anderson DG, Baillie G, Schwartz MA: Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling. Nat Cell Biol. 2016 Oct; 2016 Sep 5. PMID: 27595237
- Baeyens N, Larrivée B, Ola R, Hayward-Piatkowskyi B, Dubrac A, Huang B, Ross TD, Coon BG, Min E, Tsarfati M, Tong H, Eichmann A, Schwartz MA: Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia. J Cell Biol. 2016 Sep 26; 2016 Sep 19. PMID: 27646277
- Ahmed M, Sottnik JL, Dancik GM, Sahu D, Hansel DE, Theodorescu D, Schwartz MA: An Osteopontin/CD44 Axis in RhoGDI2-Mediated Metastasis Suppression. Cancer Cell. 2016 Sep 12; 2016 Sep 1. PMID: 27593345
- Balestrini JL, Gard AL, Gerhold KA, Wilcox EC, Liu A, Schwan J, Le AV, Baevova P, Dimitrievska S, Zhao L, Sundaram S, Sun H, Rittié L, Dyal R, Broekelmann TJ, Mecham RP, Schwartz MA, Niklason LE, White ES: Comparative biology of decellularized lung matrix: Implications of species mismatch in regenerative medicine. Biomaterials. 2016 Sep; 2016 Jun 16. PMID: 27344365
- Pawar A, Meier JA, Dasgupta A, Diwanji N, Deshpande N, Saxena K, Buwa N, Inchanalkar S, Schwartz MA, Balasubramanian N: Ral-Arf6 crosstalk regulates Ral dependent exocyst trafficking and anchorage independent growth signalling. Cell Signal. 2016 Sep; 2016 Jun 4. PMID: 27269287
- Gerhold KA, Schwartz MA: Ion Channels in Endothelial Responses to Fluid Shear Stress. Physiology (Bethesda). 2016 Sep. PMID: 27511462
- Chen Y, Lee H, Tong H, Schwartz M, Zhu C: Force regulated conformational change of integrin αVβ3. Matrix Biol. 2016 Jul 14; 2016 Jul 14. PMID: 27423389
- Kumar A, Ouyang M, Van den Dries K, McGhee EJ, Tanaka K, Anderson MD, Groisman A, Goult BT, Anderson KI, Schwartz MA: Talin tension sensor reveals novel features of focal adhesion force transmission and mechanosensitivity. J Cell Biol. 2016 May 9. PMID: 27161398
- Brenner MD, Zhou R, Conway DE, Lanzano L, Gratton E, Schwartz MA, Ha T: Spider Silk Peptide Is a Compact, Linear Nanospring Ideal for Intracellular Tension Sensing. Nano Lett. 2016 Mar 9; 2016 Feb 3. PMID: 26824190
- Dubrac A, Genet G, Ola R, Zhang F, Pibouin-Fragner L, Han J, Zhang J, Thomas JL, Chedotal A, Schwartz MA, Eichmann A: Targeting NCK-Mediated Endothelial Cell Front-Rear Polarity Inhibits Neovascularization. Circulation. 2016 Jan 26; 2015 Dec 9. PMID: 26659946
- Cuttano R, Rudini N, Bravi L, Corada M, Giampietro C, Papa E, Morini MF, Maddaluno L, Baeyens N, Adams RH, Jain MK, Owens GK, Schwartz M, Lampugnani MG, Dejana E: KLF4 is a key determinant in the development and progression of cerebral cavernous malformations. EMBO Mol Med. 2016 Jan 1. PMID: 26612856
- Baeyens N, Schwartz MA: Biomechanics of vascular mechanosensation and remodeling. Mol Biol Cell. 2016 Jan 1. PMID: 26715421
- Schwartz MA: The importance of indifference in scientific research. J Cell Sci. 2015 Aug 1; 2015 Jul 1. PMID: 26136366
- Humphrey JD, Schwartz MA, Tellides G, Milewicz DM: Role of mechanotransduction in vascular biology: focus on thoracic aortic aneurysms and dissections. Circ Res. 2015 Apr 10. PMID: 25858068
- Coon BG, Baeyens N, Han J, Budatha M, Ross TD, Fang JS, Yun S, Thomas JL, Schwartz MA: Intramembrane binding of VE-cadherin to VEGFR2 and VEGFR3 assembles the endothelial mechanosensory complex. J Cell Biol. 2015 Mar 30; 2015 Mar 23. PMID: 25800053
- Tornavaca O, Chia M, Dufton N, Almagro LO, Conway DE, Randi AM, Schwartz MA, Matter K, Balda MS: ZO-1 controls endothelial adherens junctions, cell-cell tension, angiogenesis, and barrier formation. J Cell Biol. 2015 Mar 16; 2015 Mar 9. PMID: 25753039
- Baeyens N, Nicoli S, Coon BG, Ross TD, Van den Dries K, Han J, Lauridsen HM, Mejean CO, Eichmann A, Thomas JL, Humphrey JD, Schwartz MA: Vascular remodeling is governed by a VEGFR3-dependent fluid shear stress set point. Elife. 2015 Feb 2; 2015 Feb 2. PMID: 25643397
- Daneshjou N, Sieracki N, van Nieuw Amerongen GP, Conway DE, Schwartz MA, Komarova YA, Malik AB: Rac1 functions as a reversible tension modulator to stabilize VE-cadherin trans-interaction. J Cell Biol. 2015 Jan 5. PMID: 25559184
- Bancroft T, Bouaouina M, Roberts S, Lee M, Calderwood DA, Schwartz M, Simons M, Sessa WC, Kyriakides TR: Up-regulation of thrombospondin-2 in Akt1-null mice contributes to compromised tissue repair due to abnormalities in fibroblast function. J Biol Chem. 2015 Jan 2; 2014 Nov 11. PMID: 25389299
- Conway DE, Schwartz MA: Mechanotransduction of shear stress occurs through changes in VE-cadherin and PECAM-1 tension: implications for cell migration. Cell Adh Migr. 2015; 2014 Oct 3. PMID: 25482618
- Baeyens N, Mulligan-Kehoe MJ, Corti F, Simon DD, Ross TD, Rhodes JM, Wang TZ, Mejean CO, Simons M, Humphrey J, Schwartz MA: Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling. Proc Natl Acad Sci U S A. 2014 Dec 2; 2014 Nov 17. PMID: 25404299
- Humphrey JD, Dufresne ER, Schwartz MA: Mechanotransduction and extracellular matrix homeostasis. Nat Rev Mol Cell Biol. 2014 Dec; 2014 Oct 22. PMID: 25355505
- Yan C, Liu D, Li L, Wempe MF, Guin S, Khanna M, Meier J, Hoffman B, Owens C, Wysoczynski CL, Nitz MD, Knabe WE, Ahmed M, Brautigan DL, Paschal BM, Schwartz MA, Jones DN, Ross D, Meroueh SO, Theodorescu D: Discovery and characterization of small molecules that target the GTPase Ral. Nature. 2014 Nov 20; 2014 Sep 14. PMID: 25219851
- Morrison AR, Yarovinsky TO, Young BD, Moraes F, Ross TD, Ceneri N, Zhang J, Zhuang ZW, Sinusas AJ, Pardi R, Schwartz MA, Simons M, Bender JR: Chemokine-coupled β2 integrin-induced macrophage Rac2-Myosin IIA interaction regulates VEGF-A mRNA stability and arteriogenesis. J Exp Med. 2014 Sep 22; 2014 Sep 1. PMID: 25180062
- Leerberg JM, Gomez GA, Verma S, Moussa EJ, Wu SK, Priya R, Hoffman BD, Grashoff C, Schwartz MA, Yap AS: Tension-sensitive actin assembly supports contractility at the epithelial zonula adherens. Curr Biol. 2014 Aug 4; 2014 Jul 24. PMID: 25065757
- Moissoglu K, Kiessling V, Wan C, Hoffman BD, Norambuena A, Tamm LK, Schwartz MA: Regulation of Rac1 translocation and activation by membrane domains and their boundaries. J Cell Sci. 2014 Jun 1; 2014 Apr 2. PMID: 24695858
- Schwartz M: Sticking to it: tracking the paths of integrin signalling. Nat Cell Biol. 2014 Jun. PMID: 24875734
- Humphrey JD, Milewicz DM, Tellides G, Schwartz MA: Cell biology. Dysfunctional mechanosensing in aneurysms. Science. 2014 May 2. PMID: 24786066
- Moissoglu K, Schwartz MA: Spatial and temporal control of Rho GTPase functions. Cell Logist. 2014 Apr-Jun; 2014 May 1. PMID: 25610718
- Ross TD, Coon BG, Yun S, Baeyens N, Tanaka K, Ouyang M, Schwartz MA: Integrins in mechanotransduction. Curr Opin Cell Biol. 2013 Oct; 2013 Jun 21. PMID: 23797029
- Dufresne ER, Schwartz MA: Cell migration: Towards the void. Nat Mater. 2013 Sep. PMID: 23966050
- Schwartz MA, Chen CS: Cell biology. Deconstructing dimensionality. Science. 2013 Jan 25. PMID: 23349278
- Tirziu D, Jaba IM, Yu P, Larrivée B, Coon BG, Cristofaro B, Zhuang ZW, Lanahan AA, Schwartz MA, Eichmann A, Simons M: Endothelial nuclear factor-κB-dependent regulation of arteriogenesis and branching. Circulation. 2012 Nov 27; 2012 Oct 22. PMID: 23091063
- Schwartz MA, Simons M: Lymphatics thrive on stress: mechanical force in lymphatic development. EMBO J. 2012 Feb 15; 2012 Feb 15. PMID: 22334045