title: Selective estrogen receptor modulator idoxifene inhibits smooth muscle cell proliferation, enhances reendothelialization, and inhibits neointimal formation in vivo after vascular injury.
abstract: BACKGROUND
  Idoxifene (ID) is a tissue-selective estrogen receptor modulator (SERM). The pharmacological profile of ID in animal studies suggests that it behaves like an estrogen receptor (ER) agonist in bone and lipid metabolism while having negligible ER activity on the reproductive system. It is unknown whether ID retains the vascular protective effects of estrogen.
  
  
  RESULTS
  In cultured vascular smooth muscle cells (VSMCs), ID inhibited platelet-derived growth factor-induced DNA synthesis and mitogenesis with IC(50) values of 20.4 and 27.5 nmol/L, respectively. Treatment with ID resulted in S-phase cell cycle arrest in serum-stimulated VSMCs. ID 1 to 100 nmol/L significantly protected endothelial cells from tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis in vitro. Virgin Sprague-Dawley rats ovariectomized 1 week before the study were treated with ID (1 mg x kg(-1) x d(-1)) or vehicle by gavage for 3 days before balloon denudation in carotid artery. The SMC proliferation in injured vessels was determined by immunostaining for proliferating cell nuclear antigen (PCNA). The number of PCNA-positive SMCs was reduced by 69%, 82%, and 86% in the media at days 1, 3 and 7, respectively, and by 78% in the neointima at day 7 after injury in ID- versus vehicle-treated group (P:<0.01). ID significantly enhanced reendothelialization in the injured carotid arteries as determined by Evans blue stain and immunohistochemical analysis for von Willebrand factor. In the former assay, the reendothelialized area in injured vessels was 43% in ID-treated group versus 24% in the vehicle group (P:<0.05); in the latter assay, the numbers of von Willebrand factor-positive cells per cross section increased from 24. 8 (vehicle) to 60.5 (ID) (P:<0.01) at day 14 after injury. In addition, the production of nitric oxide from excised carotid arteries was significantly higher in ID-treated than the vehicle group (8.5 versus 2.7 nmol/g, P:<0.01). Finally, ID treatment reduced neointimal area and the ratio of intima to media by 45% and 40%, respectively (P:<0.01), at day 14 after balloon angioplasty.
  
  
  CONCLUSIONS
  The results indicate that ID beneficially modulates the balloon denudation-induced vascular injury response. Inhibition of VSMC proliferation and acceleration of endothelial recovery likely mediate this protective effect of ID.
authors.affiliation: Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA, USA. Tian-Li_Yue@sbphrd.com
authors.forename: T L
authors.initials: TL
authors.lastname: Yue
authors.forename: L
authors.initials: L
authors.lastname: Vickery-Clark
authors.forename: C S
authors.initials: CS
authors.lastname: Louden
authors.forename: J L
authors.initials: JL
authors.lastname: Gu
authors.forename: X L
authors.initials: XL
authors.lastname: Ma
authors.forename: P K
authors.initials: PK
authors.lastname: Narayanan
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: B
authors.initials: B
authors.lastname: Storer
authors.forename: R
authors.initials: R
authors.lastname: Willette
authors.forename: K A
authors.initials: KA
authors.lastname: Gossett
authors.forename: E H
authors.initials: EH
authors.lastname: Ohlstein
mesh_terms: D000328:Adult; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism / Q000601:surgery; D016893:Carotid Stenosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000293:injuries* / Q000473:pathology*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010052:Ovariectomy; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology; D014949:Wounds, Nonpenetrating / Q000473:pathology*; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D020847:Estrogen Receptor Modulators; D018809:Proliferating Cell Nuclear Antigen; D014841:von Willebrand Factor; D013629:Tamoxifen; C071362:idoxifene