Up-regulation of pressure-activated Ca(2+)-permeable cation channel in intact vascular endothelium of hypertensive rats.

Abstract

In endothelial cells, stretch-activated cation channels have been proposed to act as mechanosensors for changes in hemodynamic forces. We have identified a novel mechanosensitive pressure-activated channel in intact endothelium from rat aorta and mesenteric artery. The 18-pS cation channel responded with a multifold increase in channel activity when positive pressure was applied to the luminal cell surface with the patch pipette and inactivated at negative pipette pressure. Channel permeability ratio for K+, Na+, and Ca2+ ions was 1:0.98:0.23. Ca2+ influx through the channel was sufficient to activate a neighboring Ca2+-dependent K+ channel. Hemodynamic forces are chronically disturbed in arterial hypertension. Endothelial cell dysfunction has been implicated in the pathogenesis of arterial hypertension. In two comparative studies, density of the pressure-activated channel was found to be significantly higher in spontaneously hypertensive rats and renovascular hypertensive rats compared with their respective normotensive controls. Channel activity presumably leads to mechanosensitive Ca2+ influx and induces cell hyperpolarization by K+ channel activity. Both Ca2+ influx and hyperpolarization are known to induce a vasodilatory endothelial response by stimulating endothelial nitric oxide (NO) production. Up-regulation of channel density in hypertension could, therefore, represent a counterregulatory mechanism of vascular endothelium.

Regulation of hydraulic conductivity in response to sustained changes in pressure

“…In endothelial cells, a pressure increase can stimulate stretch-activated cation channels and induce Ca 2ϩ influx that induces endothelial NO production (9). A transient increase in Ca 2ϩ also can trigger other signaling pathways that influence microvascular permeability (8,13).…”

Response of descending vasa recta to luminal pressure

“…Of interest, ␤ 1 -integrins are associated with caveolae within which caveolin and signaling complexes regulate the activity of endothelial NO synthase (15,25,35,38). Direct or indirect activation of ion channel activity has also been implicated as an endothelial mechanosensor (1,3,8,16,18,19,43). Taken together, myriad signaling pathways could account for the observed DVR endothelial response to luminal pressure.…”

Mechanosensitive Ca 2+ oscillations and STOC activation in endothelial cells

“…The activation of endothelial cells by hemodynamic forces leads to an increase in [Ca 2/ ] i (7)(8)(9), presumably via the release from intracellular stores and Ca 2/ influx into the cell. Ca 2/ influx involves Ca 2/ -permeable, mechanosensitive ion channels (7,(10)(11)(12)(13), but the regulation of intracellular Ca 2/ release under mechanical stimulation by hemodynamic forces is incompletely understood. Recently, it has been demonstrated that shear stress induces oscillatory increases in [Ca 2/ ] i (14).…”