Abstract TP269: Endothelium-dependent Vasodilation in Cerebral Resistance Arteries: Effects of Age and Estrogen Status

Introduction: The risk of cerebral vascular disease increases with age and after menopause in women. Although estrogen has positive cardiovascular effects, hormone therapy increases the risk of stroke. Importantly, our mechanistic understanding of the cerebrovascular connections between age, menopause, and estrogen replacement remains incomplete. The purpose of this study was to determine the effects of age and estrogen status on endothelium-dependent and -independent vasodilation in cerebral resistance arteries. Methods: Posterior communicating arteries (PCoA) were isolated from young, middle-aged, and old female Fisher-344 rats which were either gonadally intact, ovariectomized (OVX), or ovariectomized with estrogen replacement. Endothelium-dependent vasodilation was evaluated by assessing flow-induced vasodilation (FID) under normal, nitric oxide synthase (NOS) blockade (L-NAME), and cyclooxygenase activity inhibition conditions. Endothelium-independent vasodilation was evaluated by assessing responsiveness to an exogenous nitric oxide donor. Results: In intact rats, FID was decreased in PCoAs from old rats in comparison to those from young and middle-aged rats. This age-related deficit in FID was not influenced by OVX or L-NAME, but was further reduced when either estrogen therapy or L-NAME was given after OVX in old rats. FID was reduced by L-NAME in PCoAs from young intact rats. OVX also reduced FID in PCoAs from young rats, but L-NAME had no effect on FID after OVX. Estrogen therapy partially rescued FID in PCoA of young OVX rats only while NOS was active. In middle-aged rats, FID was reduced by OVX and not rescued by estrogen therapy. Similarly, FID in PCoAs from both intact and OXV middle-aged rats was reduced by L-NAME and not rescued by estrogen therapy. COX-mediated endothelium-dependent vasodilation and endothelium-independent vasodilation were not different in PCoAs across age and estrogen status conditions. Conclusions: We report age-specific effects of OVX and estrogen replacement on cerebrovascular function. NOS contributed to endothelium-dependent FID in PCoAs from both young and middle-aged, but not old rats. Estrogen therapy reversed OVX-induced reductions in a mechanism dependent on NOS in young rats. In old OVX rats, estrogen replacement exacerbated the age-related impairment of FID. These findings give mechanistic insight into the risk of stroke in women imposed by older age, menopause, and hormone replacement.