Integrins in the Endothelial Response to Fluid Shear Stress

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DESCRIPTION (provided by applicant): 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.