Cortistatin Inhibits Migration and Proliferation of Human Vascular Smooth Muscle Cells and Decreases Neointimal Formation upon Carotid Artery Ligation
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 suffering 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 (hAoSMCs) 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 (PDGF)-stimulated proliferation of hAoSMCs via binding to somatostatin-receptors (sst2 and sst5) and ghrelin-receptor (GHSR), induction of cAMP and p38-MAPK and inhibition of Akt activity. Moreover, cortistatin impaired lamellipodia formation and migration of hAoSMCs towards PDGF by inhibiting, in a GHSR-dependent manner, Rac-1 activation and cytosolic calcium increases. These effects on SMC proliferation and migration correlated with an inhibitory action of cortistatin on the neointimal formation in two models of carotid arterial ligation. Endogenous cortistatin seems to play a critical role in regulating SMC function since 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.
- neointimal formation
- neointimal hyperplasia
- smooth muscle cell
- Received December 12, 2012.
- Revision received April 16, 2013.
- Accepted April 17, 2013.