title: Cortistatin inhibits migration and proliferation of human vascular smooth muscle cells and decreases neointimal formation on carotid artery ligation.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Immunology and Cell Biology, Institute of Parasitology and Biomedicine Lopez-Neyra, CSIC, Granada, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Duran-Prado
authors.forename: Maria
authors.initials: M
authors.lastname: Morell
authors.forename: Virginia
authors.initials: V
authors.lastname: Delgado-Maroto
authors.forename: Justo P
authors.initials: JP
authors.lastname: Castaño
authors.forename: Jose
authors.initials: J
authors.lastname: Aneiros-Fernandez
authors.forename: Luis
authors.initials: L
authors.lastname: de Lecea
authors.forename: Michael D
authors.initials: MD
authors.lastname: Culler
authors.forename: Pedro
authors.initials: P
authors.lastname: Hernandez-Cortes
authors.forename: Francisco
authors.initials: F
authors.lastname: O'Valle
authors.forename: Mario
authors.initials: M
authors.lastname: Delgado
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008026:Ligation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D058426:Neointima / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D054440:Receptors, Ghrelin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013004:Somatostatin / Q000378:metabolism
chemical_list: D009479:Neuropeptides; D012333:RNA, Messenger; D054440:Receptors, Ghrelin; C099323:cortistatin; D013004:Somatostatin
keywords: atherosclerosis; cortistatin; migration; neointimal formation; proliferation; smooth muscle cell