Estrogen and Cerebrovascular Physiology and Pathophysiology

Abstract

ABSTRACT-Numerous studies have uncovered a wide variety of estrogen effects with apparent cardiovascular benefits, the most recognized ones being vasodilation, anti-atherogenesis, diminished post-ischemic inflammation and anti-oxidant effects. This article provides an overview of the influence of estrogen on the cerebral vasculature, under physiologic and pathophysiologic conditions, and covers both acute and chronic effects. The discussion is primarily focused on the vasodilatory and anti-inflammatory actions of estrogen, since those particular estrogen influences have received the greatest attention in studies published to date. With respect to vasodilation, although some consideration is given to the role of other vasodilating mechanisms and factors, the emphasis is mostly placed on the endothelial isoform of nitric oxide synthase, eNOS, which has emerged as a clear target of estrogen. Some consideration is given to recent findings that suggest that estrogen can stimulate eNOS activity by decreasing the expression of the eNOS inhibitor caveolin-1. With regard to the ability of estrogen to counteract inflammation, potential mechanisms by which estrogen limits the post-ischemic leukocyte adhesion, and the expression of the inducible NOS, are discussed.

Combined Endothelial Nitric Oxide Synthase Upregulation and Caveolin-1 Downregulation Decrease Leukocyte Adhesion in Pial Venules of Ovariectomized Female Rats

“…The increase in leukocyte adhesion in chronically estrogen-depleted females seen in the present and previous investigations appears to relate, at least in part, to a diminished cerebrovascular eNOS activity. However, it should be emphasized, as discussed in earlier reports, 1,2,6 that the influence of estrogen on cerebral leukocyte adhesion probably involves eNOS-independent actions as well. The documented repression of eNOS function likely relates to a downregulation of eNOS expression combined with an upregulation of the endogenous eNOS inhibitor CAV-1, since reducing leukocyte adhesion to levels seen in "estrogen-normal" females required a concomitant increase in eNOS and decrease in CAV-1 expression in cerebral venules.…”

“…3,4 NO produced in the endothelium is well known for its antiadhesive properties. 5,6 Recently, in a preliminary study, we attempted to decrease leukocyte adhesion in ovariectomized (OVX) female rats via an estrogen-independent upregulation of brain eNOS expression. Thus, experiments using chronic treatment of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin were performed.…”

Sex and limb-specific ischemic reperfusion and vascular reactivity

“…This effect has been explained by the positive influence of endogenous estrogens on the availability of NO (16), the principal vasodilator in shearmediated vasodilation (31). Indeed, numerous studies have implicated estrogen as both a prostaglandin promoter and an antioxidant (2), protecting NO from degradation and facilitating increased vasomotion (17,29,39). However, it must be noted that in the present study we standardized study visits for women to coincide with days 1-7 of the menstrual cycle, when circulating estrogen is most likely to be lowest and most similar to concentrations measured in men (16).…”

“…Indeed, epidemiologic studies have revealed that atherosclerosis, hypertension, and peripheral vascular and coronary artery diseases occur with greater prevalence in men and in postmenopausal women compared with premenopausal women (4,23,26), while clinical assessments of endotheliumdependent peripheral artery vasomotion, flow-mediated vasodilation (FMD), in healthy populations suggest that vascular function is superior in premenopausal women compared with their postmenopausal counterparts and with men (27,40,52). En masse, these studies have implicated estrogen as both a prostaglandin promoter and an antioxidant, protecting nitric oxide (NO) from degradation and facilitating increased vasomotion (29,39). Thus current knowledge suggests that female sex hormones, such as estrogen, have positive vascular effects, whereas their absence could be related to vascular dysfunction and subsequent atherogenic disease states.…”

Androgens and the cerebrovasculature: modulation of vascular function during normal and pathophysiological conditions

“…More questions than answers were generated by the Women's Health Initiative study and combined with the fact that the general population lives longer, evaluating the protective mechanisms of E2 against brain injury continues to be the objective of many ongoing studies. Several excellent reviews on cellular/molecular mechanisms involved in E2's ability to modulate cerebrovascular function under normal and diseased states are recommended to the reader as they are not discussed in this review: [66,73,96,97,99,117,118].…”