Cortistatin inhibits migration and proliferation of human vascular smooth muscle cells and decreases neointimal formation on carotid artery ligation

Circ Res. 2013 May 24;112(11):1444-55. doi: 10.1161/CIRCRESAHA.112.300695. Epub 2013 Apr 17.

Abstract

Rationale: Proliferation and migration of smooth muscle cells (SMCs) are key steps for the progression of atherosclerosis and restenosis. Cortistatin is a multifunctional neuropeptide belonging to the somatostatin family that exerts unique functions in the nervous and immune systems. Cortistatin is elevated in plasma of patients experiencing coronary heart disease and attenuates vascular calcification.

Objective: To investigate the occurrence of vascular cortistatin and its effects on the proliferation and migration of SMCs in vitro and in vivo and to delimitate the receptors and signal transduction pathways governing its actions.

Methods and results: SMCs from mouse carotid and human aortic arteries and from human atherosclerotic plaques highly expressed cortistatin. Cortistatin expression positively correlated with the progression of arterial intima hyperplasia. Cortistatin inhibited platelet-derived growth factor-stimulated proliferation of human aortic SMCs via binding to somatostatin receptors (sst2 and sst5) and ghrelin receptor, induction of cAMP and p38-mitogen-activated protein kinase, and inhibition of Akt activity. Moreover, cortistatin impaired lamellipodia formation and migration of human aortic SMCs toward platelet-derived growth factor by inhibiting, in a ghrelin-receptor-dependent manner, Rac1 activation and cytosolic calcium increases. These effects on SMC proliferation and migration correlated with an inhibitory action of cortistatin on the neointimal formation in 2 models of carotid arterial ligation. Endogenous cortistatin seems to play a critical role in regulating SMC function because cortistatin-deficient mice developed higher neointimal hyperplasic lesions than wild-type mice.

Conclusions: Cortistatin emerges as a natural endogenous regulator of SMCs under pathological conditions and an attractive candidate for the pharmacological management of vascular diseases that course with neointimal lesion formation.

Keywords: atherosclerosis; cortistatin; migration; neointimal formation; proliferation; smooth muscle cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / metabolism
  • Aorta / pathology
  • Atherosclerosis / drug therapy
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology*
  • Carotid Artery Injuries / metabolism
  • Carotid Artery Injuries / pathology*
  • Cell Movement / drug effects
  • Cell Movement / physiology
  • Cell Proliferation / drug effects
  • Humans
  • Ligation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Smooth, Vascular / cytology*
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism
  • Myocytes, Smooth Muscle / cytology*
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism
  • Neointima / drug therapy
  • Neointima / metabolism
  • Neointima / pathology*
  • Neuropeptides / genetics
  • Neuropeptides / metabolism*
  • Neuropeptides / pharmacology
  • RNA, Messenger / metabolism
  • Receptors, Ghrelin / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Somatostatin / metabolism

Substances

  • Neuropeptides
  • RNA, Messenger
  • Receptors, Ghrelin
  • cortistatin
  • Somatostatin