P2Y2 and Gq/G11 control blood pressure by mediating endothelial mechanotransduction
An elevated blood pressure is one of the key risk factors for cardiovascular diseases. Major determinants of blood pressure are vasodilatory mediators such as nitric oxide (NO) released from the endothelium under the influence of fluid shear stress exerted by the flowing blood. Previous work has identified several mechanotransducing signaling processes involved in fluid shear stress-induced endothelial effects, but how fluid shear stress initiates the response is poorly understood. Here we show in human and bovine endothelial cells that the purinergic receptor P2Y2 and the G-proteins Gq/G11 mediate fluid shear stress-induced endothelial responses such as [Ca2+]i-transients, phosphorylation of platelet-endothelial-cell-adhesion-molecule-1 (PECAM-1), vascular endothelial growth factor-2 (VEGFR-2), Src and Akt kinases as well as activation of the endothelial NO synthase (eNOS). P2Y2 is activated by ATP which is released from endothelial cells under the influence of fluid shear stress. Mice with induced endothelium-specific deficiency of P2Y2 or Gq/G11 lack flow-induced vasodilation and develop hypertension that is accompanied by reduced eNOS activation. Our data identify P2Y2 and Gq/G11 as a critical endothelial mechanosignaling pathway that is upstream of mechanotransducing processes described so far. Moreover, we demonstrate that P2Y2 and Gq/G11 are required for basal endothelial NO formation, vascular tone and blood pressure.
- Max-Planck-Institut für Herz- und Lungenforschung, Bad Nauheim
- ShengPeng Wang, PhD