Class II phosphatidylinositol 3-kinase alpha and beta isoforms are required for vascular smooth muscle Rho activation, contraction and blood pressure regulation in mice

Class II phosphatidylinositol 3-kinases (PI3K), PI3K-C2 alpha and PI3K-C2 beta, are involved in cellular processes including endocytosis, cilia formation and autophagy. However, the role of PI3K-C2 alpha and PI3K-C2 beta at the organismal level is not well understood. We found that double knockout (KO) mice with both smooth muscle-specific KO of PI3K-C2 alpha and global PI3K-C2 beta KO, but not single KO mice of either PI3K-C2 alpha or PI3K-C2 beta, exhibited reductions in arterial blood pressure and substantial attenuation of contractile responses of isolated aortic rings. In wild-type vascular smooth muscle cells, double knockdown of PI3K-C2 alpha and PI3K-C2 beta but not single knockdown of either PI3K markedly inhibited contraction with reduced phosphorylation of 20-kDa myosin light chain and MYPT1 and Rho activation, but without inhibition of the intracellular Ca2+ mobilization. These data indicate that PI3K-C2 alpha and PI3K-C2 beta play the redundant but essential role for vascular smooth muscle contraction and blood pressure regulation mainly through their involvement in Rho activation.