ESTROGEN INHIBITS THE RESPONSE-TO-INJURY IN A MOUSE CAROTID-ARTERY MODEL

The atheroprotective effects of estrogen are well documented, but the mechanisms responsible for these effects are not well understood. To s tudy the role of physiologic (nanomolar) estrogen levels on the arteri al response-to-injury, we applied a mouse carotid artery injury model to ovariectomized C57BL/6J mice. Mice were treated with vehicle (-E2, n = 10) or 17 beta-estradiol (+E2, n = 10) for 7 d, subjected to unila teral carotid injury, and 14 d later contralateral (normal = NL) and i njured carotids from -E2 and +E2 animals were pressure fixed, harveste d, and analyzed by quantitative morphometry, E2 levels in +E2 mice wer e consistently in the nanomolar range (2.1-2.5 nM) at days 0, 7, and 1 4. At 14 d, measures of both intimal and medial area were markedly inc reased in the -E2 group: (-E2 vs NL, P < 0.05 for both), but were unch anged from normal levels in the +E2 group (+E2 vs NL, P = NS and +E2 v s -E2, P < 0.05 for both). Cellular proliferation, as assessed by brom odeoxyuridine (BrdU) labeling, was significantly increased over NL in the -E2 mice, but this increase was markedly attenuated in the estroge n replacement group (total BrdU positive cells/section: NL = 6.4+/-4.5 -E2 = 113+/-26, +E2 = 40+/-3.7; -E2 vs NL, P < 0.05; +E2 vs NL, P = N S; -E2 vs +E2, P < 0.05). These data (a) demonstrate significant suppr ession of the mouse carotid response-to-injury by physiologic levels o f estrogen replacement; (b) support the utility of this model in the s tudy of the biologic effects of estrogen on the vascular-injury respon se; and (c) suggest a direct effect of estrogen on vascular smooth mus cle cell proliferation in injured vessels.