Shear-Stress-Mediated Endothelial Signaling and Vascular Homeostasis

Abstract

Endothelial cells (ECs) change their morphology, cell function, and gene expression in response to shear stress, the frictional force exerted by flowing blood. This suggests that ECs recognize shear stress and transmit signals to the interior of the cell. The molecular mechanisms of shear-stress mechanotransduction, however, are not completely understood. Our previous studies demonstrated that Ca2+ plays an important role in shear-stress-mediated endothelial signaling. When cultured human pulmonary artery ECs (HPAECs) were exposed to flow, the intracellular Ca2+ concentration increased in a shear-stress-dependent manner. The flow-induced Ca2+ response occurred in the form of an influx of extracellular Ca2+ via an ATP-operated cation channel, P2X4. We recently found that shear-stress-induced activation of P2X4 requires ATP, which is supplied in the form of endogenous ATP released by HPAECs. HPAECs released ATP in response to shear stress, and the ATP release was mediated by cell-surface ATP synthase located in caveolae/lipid rafts. At present, however, it remains unclear how shear stress activates cell-surface ATP synthase. To gain insight into the physiological role of this P2X4-meidated shear-stress mechanotransduction in vivo, we generated P2X4-deficient mice. P2X4-deficient mice do not exhibit normal EC responses to shear stress, such as Ca2+ influx and subsequent production of nitric oxide, a potent vasodilator. The vasodilation induced by acute increases in blood flow in situ is markedly suppressed in P2X4-deficient mice. P2X4-deficient mice have higher blood pressure values and excrete smaller amounts of NO products in their urine than wild-type mice. No adaptive vascular remodeling, i.e., decrease in vessel size in response to a chronic decrease in blood flow, is observed in the P2X4-deficient mice. Thus, P2X4-mediated shear-stress mechanotransduction plays an important role in the vascular homeostasis, including in the control of blood pressure and vascular remodeling.