Steroid receptor coactivator-3 is required for inhibition of neointima formation by estrogen.
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.
Yuan
Yuhui
Y
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Tex 77030, USA.
Liao
Lan
L
Tulis
David A
DA
Xu
Jianming
J
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
D004967:Estrogens; D015534:Trans-Activators; D004958:Estradiol; D051548:Histone Acetyltransferases; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3