Ovariectomy in aged versus young rats augments matrix metalloproteinase-mediated vasoconstriction in mesenteric arteries

Abstract

Ovarian deficiency is known to undermine vasoprotective mechanisms and accelerate cardiovascular disease in postmenopausal women. In a rat model of menopause (aged ovariectomized [Ovx] rats), we recently revealed a vasoconstrictor pathway mediated by matrix metalloproteinases (MMPs) via cleavage of big endothelin-1 (ET-1). However, the specific impact of aging and/or Ovx on this pathway remains unknown. We hypothesized that aging exacerbates MMP-mediated vasoconstriction in an ovary-deficient state. Young and aged female Sprague-Dawley rats, either intact or Ovx, were assessed for MMP-dependent vasoreactivity. Dose responses to big ET-1 in the absence or presence of an MMP inhibitor (GM6001) were tested on small mesenteric arteries using a pressure myograph system. MMP levels in the vascular tissue were measured by gelatin zymography. Both young Ovx and aged Ovx animals demonstrated a similar increase in the vasoconstriction to big ET-1 compared with the age-matched intact groups. MMP inhibition attenuated big ET-1 response in both Ovx groups and aged controls, but this effect was more pronounced in aged Ovx arteries (area under the curve reduction, 3.8 +/- 0.6 units in aged Ovx rats vs 1.5 +/- 0.5 units in young Ovx rats or 1.8 +/- 0.6 units in aged intact rats; P < 0.05). MMP-2 activity in the vascular tissue increased with age and was further augmented by Ovx. Regardless of age, ovarian loss increases vascular reactivity to big ET-1, which is mediated, in part, by MMP. Superimposed with advancing age, ovarian deficiency further increases the proconstrictor role of MMP, which corresponds with higher MMP-2 levels in the aging vessel wall. MMP-mediated vasoconstriction may be a mechanism contributing to vascular dysfunction in postmenopausal women.