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J Biol Chem, Vol. 273, Issue 41, 26323-26329, October 9, 1998
From the Department of Pathology, Harvard Medical School, Beth
Israel Deaconess Medical Center, Boston, Massachusetts 02215
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 specific responses within endothelial cells and serve to
modulate their intrinsic structure and function. The mechanisms by
which hemodynamic forces are detected and converted by endothelia into
a sequence of biological and even pathological responses are presently
unknown. By purifying and subfractionating the luminal endothelial cell
plasma membrane from tissue, we show, for the first time, that not only
does mechanotransduction occur at the endothelial cell surface directly
exposed to vascular flow in vivo but also increased flow
in situ induces rapid tyrosine phosphorylation of luminal
endothelial cell surface proteins located primarily in the plasmalemmal
invaginations called caveolae. Increased 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. Filipin-induced disassembly of
caveolae inhibits both proximal signaling events at the cell surface
and downstream activation of the mitogen-activated protein kinase
pathway. With the molecular machinery required for mediating rapid
flow-induced responses as seen in endothelium, caveolae may be
flow-sensing organelles converting mechanical stimuli into chemical
signals transmitted into the cell.
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