Steroid receptor coactivator-3 is required for inhibition of neointima formation by estrogen

Circulation. 2002 Jun 4;105(22):2653-9. doi: 10.1161/01.cir.0000018947.95555.65.


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.

Methods and 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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Carotid Artery Injuries / drug therapy*
  • Carotid Artery Injuries / metabolism
  • Carotid Artery Injuries / pathology
  • Cell Count
  • Cell Division / drug effects
  • Disease Models, Animal
  • Disease Progression
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Estradiol / pharmacology
  • Estrogens / pharmacology*
  • Female
  • Gene Expression
  • Gene Targeting
  • Histone Acetyltransferases
  • Immunohistochemistry
  • Ligation
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Mice, Mutant Strains
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / pathology
  • Nuclear Receptor Coactivator 3
  • Ovariectomy
  • Trans-Activators / deficiency
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Tunica Intima / drug effects*
  • Tunica Intima / injuries
  • Tunica Intima / metabolism*
  • Tunica Intima / pathology


  • Estrogens
  • Trans-Activators
  • Estradiol
  • Histone Acetyltransferases
  • Ncoa3 protein, mouse
  • Nuclear Receptor Coactivator 3