Cortistatin Inhibits Migration and Proliferation of Human Vascular Smooth Muscle Cells and Decreases Neointimal Formation on Carotid Artery Ligation

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.

WISP1 overexpression promotes proliferation and migration of human vascular smooth muscle cells via AKT signaling pathway

“…In many vascular pathological conditions including atherosclerosis and restenosis after angioplasty treatment, the abnormal proliferation and migration of VSMCs are crucial events in regulating the formation of neointimal hyperplasia, thickening of the inner layer of blood vessels (Duran-Prado et al, 2013;Miyake et al, 2011). Our previous study showed that recombinant WISP1 treatment induces proliferation and migration of rat VSMCs .…”

Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension

“…Inhibition of the Akt/mTOR signaling cascade by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) (a phosphatase that converts phosphatidylinositol 4,5-trisphosphate to phosphatidylinositol 4,5-bisphosphate, inhibiting Akt phosphorylation), rapamycin (which blocks mTOR), or Akt inhibition (specific inhibitors that bind to Akt to prevent its phosphorylation), has been well demonstrated to attenuate cell proliferation in cancer cells (64), embryonic stem cells (2,61), vascular progenitor cells (25,27), coronary arterial smooth muscle cells (9,14), and PASMC (19,20,29,49). Our previous work has also demonstrated the importance of the Akt/mTOR pathway in both thrombin-and PDGF-induced enhancement of store-operated Ca 2ϩ entry (SOCE) and cell proliferation in PASMC (44,45), whereas downregulation of transient receptor potential canonical (TRPC) channels reduced SOCE and significantly inhibit PASMC proliferation and migration (59,72).…”

Blockade of Urotensin II Receptor Prevents Vascular Dysfunction

“…The proliferation of VSMCs is the main phase for the progression of atherosclerosis and restenosis (Duran-Prado et al ., 2013). Herein, the effects of KR-36676 on the proliferation of UII (50 nM)-stimulated hAoSMCs were assessed through analysis of DNA synthesis using the incorporation of BrdU.…”

“…The activation of MAPK is known to have critical role in the UII-induced proliferation of VSMCs (Djordjevic et al ., 2005; Duran-Prado et al ., 2013). Therefore, the effects of inhibitors of p38 MAPK, JNK, and ERK1/ on VSMC proliferation were examined.…”