Downregulation of natriuretic peptide receptor-C in vascular smooth muscle cells from spontaneously hypertensive rats contributes to vascular remodeling.

ABSTRACT

Hypertension is associated with vascular remodeling due to hyperproliferation and hypertrophy of vascular smooth muscle cells (VSMC). VSMC from several animal models of hypertensive rats including spontaneously hypertensive rats (SHR) exhibit hyperproliferation, hypertrophy and decreased expression of natriuretic peptide receptor-C (NPR-C). In addition, angiotensin II (Ang II) and growth factors that promotes vascular remodeling have also been shown to attenuate the expression of NPR-C in VSMC. The present study investigates the relationship between the decreased expression of NPR-C and vascular remodeling in SHR and the underlying molecular mechanisms. Aortic VSMC from SHR and their control Wistar Kyoto (WKY) rats were transfected with cDNA of NPR-C and used for the vascular remodeling studies. Transfection of VSMC with cDNA of NPR-C augmented the expression of NPR-C in both VSMC from SHR and WKY rats and resulted in the attenuation of hyperproliferation and hypertrophy of VSMC from SHR. The overexpression of NPR-C also resulted in the attenuation of increased expression of epidermal growth factor receptor (EGFR), platelet derived growth factor receptor (PDGFR), cell cycle proteins, cyclin D1, cyclin-dependent kinase 4 (Cdk4), phospho-retinoblastoma (pRb) and Giα-2 proteins, all these signaling molecules implicated in the hyperproliferation/hypertrophy of VSMC from SHR. In summary, these results indicate that augmenting the decreased expression of NPR-C in VSMC from SHR improves vascular remodeling by attenuating hyperproliferation and hypertrophy through decreasing the overexpression of several signaling molecules. It may be suggested that NPR-C plays a vasculoprotective role and that the downregulation of NPR-C contributes to the vascular remodeling in SHR.