Endothelial function is most commonly assessed as a vasodilatory response to pharmacological or mechanical stimuli. Increased blood-flow shear (flow-mediated) is a mechanical means to stimulate vasodilation through NO release (29). The most com monly used clinical measure is high-frequency ultrasound assessed branchial artery diameter changes after blood pressure (BP) cuff-induced hyperemia (30). An assessment of nonendothelium-dependent vasodilation by use of nitroglycerin or nitroprusside is usually performed concomitantly to assess nonspecific smooth muscle effects.
The onset of menopause provides a natural model of estrogen deprivation in which the effects of the endogenous hormone on vascular function can be evaluated. In studies of changes in branchial artery diameter after reactive hyperemia, responses were greater in premenopausal than in postmenopausal women (31). Importantly, blood-flow responses to the NO donor glyceryl trinitrate (GTN) were similar in the two groups, indicating comparable vascular smooth muscle responses to NO. The responses in postmenopausal women were comparable to those observed in men (31). In agreement with these findings, sex hormone deprivation after ovariectomy or premature ovarian failure, is associated with a decline in endothelial-dependent vasodilation, whereas the response to GTN is unaltered (32,33). Another natural model of changes in estrogen levels is the menstrual cycle. In young women, endothelium-dependent vasodilation in the branchial artery paralleled serum estradiol levels, and furthermore, there was evidence of progesterone antagonism of this effect (34,35).
ERT also provides insights into NO regulation by estrogen. Thus, endothelium-depen-dent vasodilation of the branchial and coronary arteries is enhanced after ERT in postmenopausal women and levels of plasma NO and NO metabolites are increased (36,37). It is of interest that inclusion of progesterone in postmenopausal HRT may blunt the effects of estrogen on endothelial NO production (38). Similar effects of enhanced endot-helial function have been observed after ERT in young women with premature ovarian failure or following ovariectomy and in young women receiving oral contraception (33,39). Furthermore, a case has been reported of a young man with nonfunctional ERa as a result of mutation of the ER gene (40). The man was found to have impaired branchial endothelium-dependent relaxation and early coronary calcification supporting the view that ERa is important for endothelial NO release.
The mechanism by which estrogen exposure improves endothelial function is at least partially mediated by an enhancement of NO production by the endothelial isoform of nitric oxide synthase (eNOS) as a result of an increase in both eNOS expression and level of activation. The effects are primarily mediated at the level of gene transcription, and are dependent on ERs that classically serve as transcription factors (28,41). Apart from the long-term effects of estrogen on the vasculature through gene expression (genomic effects), there is evidence that estrogen can cause short-term rapid vasodilation by both endothelium-dependent and endothelium-independent pathways (41). These rapid effects do not appear to involve changes in gene expression (nongenomic or nontranscriptional effects). Thus, estrogen dilates coronary and branchial arteries within minutes when administered intravenously or intra-arterially to postmenopausal women (42).
Recent studies suggest that the rapid effects of estrogen on vascular cells could be mediated by a subpopulation of ERa localized to caveolae in endothelial cells, in which they are coupled to eNOS in a functional signaling module, in a nongenomic manner (22). These observations provide evidence for the existence of a steroid receptor fast-action complex in caveolae. Estrogen binding to ERa within caveolae leads to Gai activation, which mediates downstream events. The downstream signaling includes activation of tyrosine kinase-mitogen-activated protein kinase and Akt/protein kinase B signaling, stimulation of heat shock protein-90 binding to eNOS, and changes in the local calcium environment, ultimately leading to eNOS stimulation (43-45). Additional mechanisms for nongenomic estrogen-induced vasodilation are found in the potent and rapid regulation of Ca2+ mobilization and in the control of the cell membrane K+ channels in vascular smooth muscle cells (VSMCs), that produce vessel relaxation and increased blood flow (46).
Other important factors released from the vascular endothelium include prostacyclin, a potent vasodilator and platelet inhibitor, and endothelin-1, a potent vasoconstrictor. Estrogen administration stimulates prostacyclin but inhibits production of endothelin in human vascular endothelial cells (47). Estrogen also inhibits apoptosis of cultured human endothelial cells in an ER-dependent manner (48). Additionally, estrogen directly inhibits the migration and proliferation of SMCs in vitro, and the expression of adhesion molecules by vascular cells (49,50). Thus, estrogen contributes to long-term vascular health by inhibiting the proliferation of VSMC and accelerating the growth of endothelial cells.
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