Abstract
Angiotensin II (AngII) is a crucial hormone that affects vasoconstriction and exerts hypertrophic effects on vascular smooth muscle cells. Here, we showed that phosphatidylinositol 3-kinase-dependent calcium mobilization plays pivotal roles in AngII-induced vascular constriction. Stimulation of rat aortic vascular smooth muscle cell (RASMC)-embedded collagen gel with AngII rapidly induced contraction. AngII-induced collagen gel contraction was blocked by pretreatment with a phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002) whereas ERK inhibitor (PD98059) was not effective. AngII-induced collagen gel contraction was significantly blocked by extracellular calcium depletion by EGTA or by nifedipine which is an L-type calcium channel blocker. In addition, AngII-induced calcium mobilization was also blocked by nifedipine and EGTA, whereas intracellular calcium store-depletion by thapsigargin was not effective. Finally, pretreatment of rat aortic ring with LY294002 and nifedipine significantly reduced AngII-induced constriction. Given these results, we suggest that PI3K-dependent activation of L-type calcium channels might be involved in AngII-induced vascular constriction.
Highlights
The renin-angiotensin system (RAS) plays crucial roles in many physiological processes
Since phosphatidylinositol 3-kinase (PI3K) is involved in the Angiotensin II (AngII)-induced calcium mobilization of smooth muscle cells from portal vein (Viard et al, 1999), we examined the possible role of PI3K in vascular smooth muscle cell (VSMC) contractions
Since calcium mobilization is important for smooth muscle cell contraction, we examined the effect of calcium channel blocker on AngII-induced rat aortic vascular smooth muscle cell (RASMC) contractions
Summary
The renin-angiotensin system (RAS) plays crucial roles in many physiological processes. Acute roles for AngII have been implicated in the regulation of plasma volume control, vasoconstriction, and blood pressure control, whereas chronic stimulation with AngII induces hyperplasia and hypertrophy of vascular smooth muscle cells (VSMCs) (Geisterfer et al, 1988). Occupation of AT1R by AngII results in intracellular calcium mobilization, which binds to calmodulin and activates myosin light chain kinase (MLCK). Activated MLCK eventually leads to the phosphorylation of the myosin light chain which causes it to interact with actin, causing contraction of VSMCs (Yan et al, 2003). MLCK is negatively regulated by myosin light chain phosphatase (MLCP), which is inactivated by Rho kinase. Activation of the Rho kinase signaling pathway leads to sustained contraction of VSMCs (Uehata et al, 1997). Intracellular calcium mobilization is a key mediator of VSMC contraction
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