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1 Center for Cardiovascular Science, Albany Medical College, Albany, NY, USA; Vascular Biology and Angiogenesis Program, Sidney Kimmel Cancer Center, San Diego, CA, USA
2 Center for Cardiovascular Science, Albany Medical College, Albany, NY, USA
3 Biomedical Engineering, Rensselaer Polytechnic, Troy, NY, USA
4 Vascular Biology and Angiogenesis Program, Sidney Kimmel Cancer Center, San Diego, CA, USA
* To whom correspondence should be addressed. E-mail: rizzov{at}mail.amc.edu.
The luminal surface of rat lung microvascular endothelial cells in situ is sensitive to changing hemodynamic parameters. Acute mechano-signaling events initiated in response to flow changes in perfused lung microvessels are localized within specialized invaginated microdomains called caveolae. Here we report that chronic exposure to shear stress alters caveolin expression and distribution, increases caveolae density and leads to enhanced mechano-sensitivity to subsequent changes in hemodynamic forces within cultured endothelial cells. Flow-preconditioned cells expressed a 5-fold increase in caveolin (and other caveolar residing proteins) at the luminal surface compared to no-flow controls. The density of morphologically identifiable caveolae was enhanced 6-fold at the luminal cell surface of flow-conditioned cells. Laminar shear stress applied to static endothelial cultures (flow-step of 5 dyn/cm2) enhanced the tyrosine phosphorylation of luminal surface proteins by 1.7-fold, including caveolin-1 (1.3-fold), increased Ser1179 phosphorylation of eNOS by 2.6-fold and induced a 1.4-fold activation of ERK 1/2 over no-flow controls. The same shear-step applied to endothelial cells preconditioned under 10 dyn/cm2 of laminar shear stress for 6 hrs induced a 7-fold increase of total phosphotyrosine signal at the luminal endothelial cell surface, enhanced caveolin-1 tyrosine phosphorylation 5.8-fold and eNOS phosphorylation by 3.3-fold over static control values. In addition, phosphorylated caveolin-1 and eNOS proteins were preferentially localized to caveolar microdomains. In contrast, ERK 1/2 activation was not detected in conditioned cells after acute shear challenge. These data suggest that cultured endothelial cells respond to a sustained flow environment by directing caveolae to the cell surface where they serve to mediate, at least in part, mechanotransduction responses
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