RAPID MECHANOTRANSDUCTION IN-SITU AT THE LUMINAL CELL-SURFACE OF VASCULAR ENDOTHELIUM AND ITS CAVEOLAE

The vascular endothelium is uniquely positioned between the blood and tissue compartments to receive directly the fluid forces generated by the blood flowing through the vasculature. These forces invoke specifi c responses within endothelial cells and serve to modulate their intri nsic structure and function. The mechanisms by which hemodynamic force s are detected and converted by endothelia into a sequence of biologic al and even pathological responses are presently unknown. By purifying and subfractionating the luminal endothelial cell plasma membrane fro m tissue, we show, for the first time, that not only does mechanotrans duction occur at the endothelial cell surface directly exposed to vasc ular flow in, vivo but also increased flow in situ induces rapid tyros ine phosphorylation of luminal endothelial cell surface proteins locat ed primarily in the plasmalemmal invaginations called caveolae. Increa sed flow induces the translocation of signaling molecules primarily to caveolae, ultimately activating the Ras-Raf-mitogen-activated protein kinase pathway. This signaling appears to require intact caveolae. Fi lipin-induced disassembly of caveolae inhibits both proximal signaling events at the cell surface and downstream activation of the mitogen-a ctivated protein kinase pathway. With the molecular machinery required for mediating rapid flow-induced responses as seen in endothelium, ca veolae may be flow-sensing organelles converting mechanical stimuli in to chemical signals transmitted into the cell.