Natriuretic peptide receptor-3 underpins the disparate regulation of endothelial and vascular smooth muscle cell proliferation by C-type natriuretic peptide

Br J Pharmacol. 2011 Sep;164(2b):584-97. doi: 10.1111/j.1476-5381.2011.01400.x.


Background and purpose: C-type natriuretic peptide (CNP) is an endothelium-derived vasorelaxant, exerting anti-atherogenic actions in the vasculature and salvaging the myocardium from ischaemic injury. The cytoprotective effects of CNP are mediated in part via the G(i) -coupled natriuretic peptide receptor (NPR)3. As GPCRs are well-known to control cell proliferation, we investigated if NPR3 activation underlies effects of CNP on endothelial and vascular smooth muscle cell mitogenesis.

Experimental approach: Proliferation of human umbilical vein endothelial cells (HUVEC), rat aortic smooth muscle cells (RAoSMC) and endothelial and vascular smooth muscle cells from NPR3 knockout (KO) mice was investigated in vitro.

Key results: CNP (1 pM-1 µM) facilitated HUVEC proliferation and inhibited RAoSMC growth concentration-dependently. The pro- and anti-mitogenic effects of CNP were blocked by the NPR3 antagonist M372049 (10 µM) and the extracellular signal-regulated kinase (ERK) 1/2 inhibitor PD98059 (30 µM) and were absent in cells from NPR3 KO mice. Activation of ERK 1/2 by CNP was inhibited by Pertussis toxin (100 ng·mL⁻¹) and M372049 (10 µM). In HUVEC, ERK 1/2 activation enhanced expression of the cell cycle promoter, cyclin D1, whereas in RAoSMC, ERK 1/2 activation increased expression of the cell cycle inhibitors p21(waf1/cip1) and p27(kip1) .

Conclusions and implications: A facet of the vasoprotective profile of CNP is mediated via NPR3-dependent ERK 1/2 phosphorylation, resulting in augmented endothelial cell proliferation and inhibition of vascular smooth muscle growth. This pathway may offer an innovative approach to reversing the endothelial damage and vascular smooth muscle hyperplasia that characterize many vascular disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Growth Processes / physiology
  • Cells, Cultured
  • Cyclic GMP / metabolism
  • Cyclin D1 / metabolism
  • Endothelial Cells / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Flavonoids / pharmacology
  • Human Umbilical Vein Endothelial Cells / cytology
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Muscle, Smooth, Vascular / cytology*
  • Muscle, Smooth, Vascular / metabolism
  • Myocytes, Smooth Muscle / metabolism*
  • Natriuretic Peptide, C-Type / metabolism*
  • Oligopeptides / pharmacology
  • Phosphorylation / physiology
  • Quinoxalines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Atrial Natriuretic Factor / genetics
  • Receptors, Atrial Natriuretic Factor / metabolism*
  • Signal Transduction / physiology


  • CCND1 protein, human
  • Cell Cycle Proteins
  • Flavonoids
  • M 372049
  • Oligopeptides
  • Quinoxalines
  • Natriuretic Peptide, C-Type
  • Cyclin D1
  • Extracellular Signal-Regulated MAP Kinases
  • Receptors, Atrial Natriuretic Factor
  • atrial natriuretic factor receptor C
  • Cyclic GMP
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one