C-type natriuretic peptide induces redifferentiation of vascular smooth muscle cells with accelerated reendothelialization

We recently reported that C-type natriuretic peptide (CNP) occurs in vascul ar endothelial cells and acts as a vascular-type natriuretic peptide. In th e present study, we stimulated the cGMP cascade in proliferating smooth mus cle cells (SMCs), in which particulate guanylate cyclase-B, the specific re ceptor for CNP, is predominantly expressed, by use of an adenovirus encodin g rat CNP cDNA (Ad.CNP). In the Ad.CNP-treated cultured SMCs, CNP caused th e growth inhibition of SMCs at G, phase with an early increase of p21(CIP1/ WAF1) expression and subsequent upregulation of p16(INK4a). The expression of smooth muscle myosin heavy chain-2, which is the molecular marker of hig hly differentiated SMCs, was reinduced in the Ad,CNP-treated SMCs, The Ad,C NP-treated SMCs also reexpressed particulate guanylate cyclase-A, which sho ws high affinity to atrial and brain natriuretic peptide and is exclusively expressed in well-differentiated SMCs. CNP, which was overexpressed in rab bit femoral arteries in vivo at the time of balloon injury, significantly s uppressed neointimal formation. Furthermore, an enhancement of the expressi on of smooth muscle myosin heavy chain-2 occurred in the residual neointima . In addition, early regeneration of endothelial cells was observed in the Ad.CNP-infected group. Thus, stimulation of cGMP cascade in proliferating d edifferentiated SMCs can induce growth inhibition and redifferentiation of SMCs with accelerated reendothelialization.