Endothelial cell gene expression and behavior is highly regulated by fluid shear stress from flowing blood. Endothelial responses to flow regulate vascular embryogenesis, normal vascular physiology and development of atherosclerosis. Our previous work identified a mechanotransduction complex consisting of PECAM-1, VE-cadherin and VEGF receptor 2 that resides at cell-cell junctions and mediates conversion of force to biochemical signals in this system. PECAM-1 appears to be the true force transducer, VE-cadherin functions as an adapter that brings VEGFR2 into the complex and the VEGFR tyrosine kinase initiates key downstream signals. These signals include conversion of integrins to high affinity states, which leads to their binding to extracellular matrix. These newly bound integrins then generate signals. Consistent with this model, the extracellular matrix under the endothelial cells critically modulates the signals induced by flow. In particular, PAK (p21-activated kinase) mediates critical aspects of this matrix specificity. The current project aims to elucidate the molecular mechanism for transduction by the junctional mechanotransduction complex and to test the role of PAK in atherogenesis in vivo. To achieve these overall goals we will: 1) measure forces across PECAM-1 and elucidate the role of the PECAM-1 cytoplasmic domain in mechanotransduction. 2) identify the protein interactions that mediate adapter function by VE-cadherin. 3) examine vascular inflammation and atherogenesis in PAK-deficient mice.

Public Health Relevance

Atherosclerosis is a chronic inflammatory disease of arteries. Approximately half of all deaths in the United States are caused by heart attacks, strokes or other vascular events associated with atherosclerosis. While risk factors such as hyperlipidemia and diabetes are important risk factors, atherosclerosis is initiated and maintained at regions of arteries that are subject to disturbances in fluid flow. This project will investigate the molecular mechanisms of mechanotransduction in arteries that leads to atherosclerosis. Understand how fluid shear stress induces vascular inflammation is likely to identify new drug targets that may lead to more effective therapies to prevent or treat these diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075092-10
Application #
8254438
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Kindzelski, Andrei L
Project Start
2003-12-29
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2013
Total Cost
$392,111
Indirect Cost
$156,491
Name
Yale University
Department
None
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Conway, Daniel E; Schwartz, Martin A (2013) Flow-dependent cellular mechanotransduction in atherosclerosis. J Cell Sci 126:5101-9
Conway, Daniel E; Breckenridge, Mark T; Hinde, Elizabeth et al. (2013) Fluid shear stress on endothelial cells modulates mechanical tension across VE-cadherin and PECAM-1. Curr Biol 23:1024-30
Wang, Chong; Baker, Brendon M; Chen, Christopher S et al. (2013) Endothelial cell sensing of flow direction. Arterioscler Thromb Vasc Biol 33:2130-6
Wang, Chong; Lu, Hao; Schwartz, Martin Alexander (2012) A novel in vitro flow system for changing flow direction on endothelial cells. J Biomech 45:1212-8
Hoffman, Brenton D; Grashoff, Carsten; Schwartz, Martin A (2011) Dynamic molecular processes mediate cellular mechanotransduction. Nature 475:316-23
Hahn, Cornelia; Wang, Chong; Orr, A Wayne et al. (2011) JNK2 promotes endothelial cell alignment under flow. PLoS One 6:e24338
Funk, Steven Daniel; Yurdagul Jr, Arif; Green, Jonette M et al. (2010) Matrix-specific protein kinase A signaling regulates p21-activated kinase activation by flow in endothelial cells. Circ Res 106:1394-403
Petzold, Tobias; Orr, A Wayne; Hahn, Cornelia et al. (2009) Focal adhesion kinase modulates activation of NF-kappaB by flow in endothelial cells. Am J Physiol Cell Physiol 297:C814-22
Hahn, Cornelia; Orr, A Wayne; Sanders, John M et al. (2009) The subendothelial extracellular matrix modulates JNK activation by flow. Circ Res 104:995-1003
Hahn, Cornelia; Schwartz, Martin A (2009) Mechanotransduction in vascular physiology and atherogenesis. Nat Rev Mol Cell Biol 10:53-62

Showing the most recent 10 out of 23 publications