Estrogen replacement increases matrix metalloproteinase contribution to vasoconstriction in a rat model of menopause

Abstract

OBJECTIVE: Estrogen deficiency has been implicated in the pathogenesis of postmenopausal hypertension; yet hormone replacement therapy has controversial effects on the cardiovascular risk. Surprisingly, the effects of estrogen in the aging vascular system have been understudied. Aging is associated with vascular inflammation [elevated tumor necrosis factor (TNF)]. TNF is an activator of matrix metalloproteinases (MMPs) that can have vasoactive properties by specific cleavage of big endothelin-1 (ET-1). We hypothesized that MMPs are downstream mediators of vascular dysfunction in aging/estrogen deficiency. METHODS: Aged rats (12 months) were ovariectomized (to model a menopausal phenotype) and treated with placebo, estrogen or TNF inhibitor (etanercept) for 4 weeks. Reactivity of resistance mesenteric arteries was evaluated on pressure arteriograph and vascular MMP activity measured by gelatin zymography. RESULTS: Vasoconstriction to big ET-1 was greater in menopausal (relative to cycling) phenotype, but attenuated with MMP inhibition. Estrogen replacement reduced sensitivity to big ET-1, whereas further increased the role of MMP in the constriction, which was not mediated by TNF. MMP-2 activity in the mesenteric vascular bed was greater in menopausal compared with cycling females, but returned to control levels after estrogen treatment. CONCLUSIONS: Our study indicates that MMPs are critical modulators of endothelin-mediated vasoconstriction in aging/estrogen deficiency that was not evident in cycling animals. Estrogen replacement is complex: although it reduces MMP expression, estrogen leads to a greater acute MMP modulation of vascular function. Thus, understanding the novel role of estrogen as a regulator of vascular MMPs may provide valuable insights into women's cardiovascular health issues in aging.