The anti‐atherogenic potential of C‐type natriuretic peptide: Disparate regulation of endothelial and vascular smooth muscle cell proliferation via natriuretic peptide receptor‐C

Abstract

C‐type natriuretic peptide (CNP) is an endothelium‐derived mediator that exerts an anti‐atherosclerotic influence on the blood vessel wall. Herein, we examined whether the cytoprotective activity of CNP might be mediated, in part, via opposing effects on endothelial and vascular smooth muscle cell proliferation.CNP increased human umbilical vein endothelial cell (HUVEC) proliferation but inhibited rat aortic smooth muscle cell (RAoSMC) growth; both effects were blocked by the selective natriuretic peptide receptor (NPR)‐C antagonist M372049 and the extracellular signal regulated kinase (ERK) 1/2 inhibitor PD98059. The effects of CNP on cell proliferation were also lost in endothelial and vascular smooth muscle cells from NPR‐C knockout mice. In both HUVEC and RAoSMC, CNP caused ERK 1/2 phosphorylation in a M372049‐inhibitable manner. In HUVEC, CNP‐dependent ERK 1/2 activation resulted in enhanced expression of the cell cycle promoter, cyclin D1, and concomitantly decreased expression of the cell cycle inhibitor, p21. In contrast, in RAoSMC ERK 1/2 activation by CNP was accompanied by increased expression of the cell cycle inhibitors p21 and p27.These data show that CNP can up‐regulate endothelial cell proliferation yet inhibit vascular smooth muscle cell growth via the same receptor, NPR‐C. Such findings highlight further the anti‐atherogenic ability of CNP.Funded by the Wellcome Trust