title: Steroid receptor coactivator-3 is required for inhibition of neointima formation by estrogen.
abstract: BACKGROUND
  The vasoprotective effects of estrogen are mediated by estrogen receptors (ERs). ERs are transcription factors that require coactivators to exert transcriptional activity. The steroid receptor coactivator-3 (SRC-3, also known as pCIP, AIB1, ACTR, and TRAM-1) interacts with estrogen-bound ERs and strongly coactivates the transcription of target genes in cultured cells. This study has characterized the expression of SRC-3 in cardiovascular tissue and the role of SRC-3 in estrogen-dependent vasoprotection from vascular injury.
  
  
  RESULTS
  Phenotypically normal SRC-3(+/-) mice with a knock-in LacZ reporter were used to characterize SRC-3 expression by X-gal staining within the cardiovascular system. Staining signals were specifically detected in vascular smooth muscle cells and endothelial cells but not in myocardial cells. The role of SRC-3 during vascular remodeling was analyzed using a unilateral carotid ligation model. The extent of neointima formation in SRC-3(-/-) mice was significantly higher than in wild-type mice, and this difference was diminished after depletion of estrogen by ovariectomy. After ovariectomy, neointimal growth in wild-type mice was almost completely inhibited by estrogen treatment but only partially inhibited in SRC-3(-/-) mice. Furthermore, estrogen treatment resulted in reduced inhibition of intimal cell proliferation in SRC-3(-/-) mice.
  
  
  CONCLUSIONS
  SRC-3 is highly expressed in vascular smooth muscle cells and endothelial cells. The loss of SRC-3 function causes a decrease in sensitivity of estrogen-mediated inhibition of neointimal growth, which may be attributable to an insufficient suppression of vascular cell proliferation. These results indicate that SRC-3 largely facilitates ER-dependent vasoprotective effects under conditions of vascular trauma.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Tex 77030, USA.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Yuan
authors.forename: Lan
authors.initials: L
authors.lastname: Liao
authors.forename: David A
authors.initials: DA
authors.lastname: Tulis
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression; D018390:Gene Targeting; D051548:Histone Acetyltransferases; D007150:Immunohistochemistry; D008026:Ligation; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D056921:Nuclear Receptor Coactivator 3; D010052:Ovariectomy; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017539:Tunica Intima / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism* / Q000473:pathology
chemical_list: D004967:Estrogens; D015534:Trans-Activators; D004958:Estradiol; D051548:Histone Acetyltransferases; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3