© 1997 by European Society of Cardiology
Copyright © 1997, European Society of Cardiology
Mechanisms of natriuretic-peptide-induced growth inhibition of vascular smooth muscle cells
Falk Cardiovascular Research Center, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA
* Corresponding author. Current address: Laboratory of Genetic Physiology, Brigham and Women's Hospital, Thorn-12, 75 Francis Street, Boston, MA 02115, USA. Tel.: +1 (617) 732-8799; fax: +1 (617) 975-0995; e-mail: rpratt@bustoff.bwh.harvard.edu
Objective: While natriuretic peptides can inhibit growth of vascular smooth muscle cells (VSMC), controversy exists as to whether this effect is mediated via the guanylate cyclase-coupled receptors, NPR-A and NPR-B, or the clearance receptor, NPR-C. The original aim of this study was to examine the mechanism by which the NPR-C receptor regulates growth. Methods: Rat VSMC were characterized with regard to natriuretic peptide receptor expression by RT/PCR and radioligand binding studies. The effect on growth following addition of the peptides and the ligands for NPR-C was measured by [3H]thymidine incorporation. Cyclic guanosine monophosphate (cGMP) levels were determined by radioimmunoassay and mitogen activating protein kinase activity was based on the phosphorylation of myelin basic protein. Results: In rat VSMC, passages 4–12, both atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) dose-dependently inhibited serum and PDGF-induced VSMC growth. In contrast, NPR-C specific ligands alone had no effect on cell growth but enhanced growth inhibition when co-administered with ANP and CNP. ANP and CNP also decreased PDGF-BB-stimulated MAP kinase activity. Once again, NPR-C specific ligands alone had no effect but enhanced the effects of ANP. Furthermore, a cGMP specific phosphodiesterase inhibitor dose-dependently inhibited VSMC growth and markedly enhanced natriuretic-peptide-induced inhibition at low peptide concentrations. To examine a potential mechanism for the controversy concerning the NPR-C, we investigated the autocrine expression of ANP and CNP by VSMC and found that mRNA encoding both peptides could be detected by RT/PCR. Conclusion: Our findings indicate that the guanylyl-cyclase-linked receptors mediate the antiproliferative actions of the natriuretic peptides on vascular smooth muscle cell growth. Moreover, we hypothesize that the apparent inhibition of growth by NPR-C specific ligands reported by others may be due to stabilization of natriuretic peptides produced by the cultured VSMC and subsequent action of these peptides at guanylyl-cyclase-linked receptors.
KEYWORDS ANP; Growth; Radioimmune assay; cGMP; MAP kinase; Receptors; Vascular smooth muscle cell proliferation; Rat, vascular smooth muscle cells
1 Current address: Cardiovascular and Licensing, Zeneca Pharmaceuticals, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850, USA.
2 Current address: Centre de Cardiologie, Hôpital Cantonal Universitaire de Genève, 24, rue Micheli-du-Crest, 1211 Geneva 4, Switzerland.
3 Current address: Cardiovascular Research Department, Genentech, Inc., 460 Point San Bruno Boulevard, South San Francisco, CA 94080, USA.
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