Effect of estrogen on cerebrovascular prostaglandins is amplified in mice with dysfunctional NOS

Abstract

. Effect of estrogen on cerebrovascular prostaglandins is amplified in mice with dysfunctional NOS. Am J Physiol Heart Circ Physiol 287: H588 -H594, 2004. 10.1152/ajpheart. 01176.2003.-Chronic estrogen treatment increases endothelial vasodilator function in cerebral arteries. Endothelial nitric oxide (NO) synthase (eNOS) is a primary target of the hormone, but other endothelial factors may be modulated as well. In light of possible interactions between NO and prostaglandins, we tested the hypothesis that estrogen treatment increases prostanoid-mediated dilation using NOS-deficient female mouse models, i.e., mice treated with a NOS inhibitor [N G -nitro-L-arginine methyl ester (L-NAME)] for 21 days or transgenic mice with the eNOS gene disrupted (eNOS Ϫ/Ϫ ). All mice were ovariectomized; some in each group were treated chronically with estrogen. Cerebral blood vessels then were isolated for biochemical and functional analyses. In vessels from control mice, estrogen increased protein levels of eNOS but had no significant effect on cyclooxygenase (COX)-1 protein, prostacyclin production, or constriction of pressurized, middle cerebral arteries to indomethacin, a COX inhibitor. In L-NAME-treated mice, however, cerebrovascular COX-1 levels, prostacyclin production, and constriction to indomethacin, as well as eNOS protein, were all greater in estrogen-treated animals. In vessels from eNOS Ϫ/Ϫ mice, estrogen treatment also increased levels of COX-1 protein and constriction to indomethacin, but no effect on prostacyclin production was detected. Thus cerebral blood vessels of control mice did not exhibit effects of estrogen on the prostacyclin pathway. However, when NO production was dysfunctional, the impact of estrogen on a COX-sensitive vasodilator was revealed. Estrogen has multiple endothelial targets; estrogen effects may be modified by interactions among these factors.cyclooxygenase-1; prostacyclin; indomethacin; endothelial nitric oxide synthase; N G -nitro-L-arginine methyl ester ESTROGEN DECREASES VASCULAR REACTIVITY through endothelial mechanisms (3,9,10,16,32,35,42). The endothelium releases multiple factors to regulate smooth muscle tone, including vasodilators nitric oxide (NO), prostacyclin (PGI 2 ), and hyperpolarizing factors (EDHF). Evidence suggests estrogen can increase one or more of these vasodilator pathways, depending on the particular blood vessel or vascular bed studied (9,16,32,35,42). Local interaction among endothelial factors (3, 7, 16), however, may also be an important variable that influences vascular actions of estrogen. When NO formation is disrupted, there is often compensatory upregulation of either PGI 2 (2, 21, 31, 34, 41) or EDHF (16) that can be affected by sex steroids (3,10,16). This compensation is thought to be a protective mechanism for maintaining endothelium-dependent vasodilation (7). However, various examples of cross-talk between endothelial dilators indicate that the nature and mechanisms involved may vary depending on the vessel and conditions studied (1, 6 -8, 13, 2...

Vascular Actions of Estrogens: Functional Implications

“…In cerebral vessels from control mice treated with estrogen, eNOS was up-regulated, but there were no effects of estrogen treatment on cyclooxygenase-1, production of prostacyclin, or constriction to indomethacin. In contrast, in animals with dysfunctional NOS, either eNOS knockouts or animals treated chronically with a NOS inhibitor (Li et al, 2004), all three parameters were enhanced after estrogen treatment. Emphasizing the diversity of endothelial function in different vascular beds in arteries from skeletal muscles of rats treated with a NOS inhibitor, estrogen treatment increased vasodilatation mediated by endotheliumderived hyperpolarizing factor .…”

Testosterone treatment increases thromboxane function in rat cerebral arteries

“…Many studies suggest that NO modulates vascular prostanoid production (3,22,38,42), which may explain why block of NO synthesis allowed us to study the contribution of TxA 2 to basal tone. Similarly, inhibition of NO production was found to enhance the prostacyclin prostanoid pathway in cerebral blood vessels (24).…”

Cerebral Blood Flow Regulation by Nitric Oxide: Recent Advances

“…It seems that vascular Rho-kinase function is suppressed by estrogen in female rats, and the higher NO activity in females is estrogen-independent. In cerebral blood vessels from control mice, chronic treatment with estrogen increased protein levels of eNOS but had no effect on COX-1 protein and PGI 2 production, in L-NAMEtreated mice, cerebrovascular COX-1 levels and PGI 2 production, as well as eNOS protein, were greater in estrogen-treated animals, and in vessels from eNOSknockout mice, estrogen also increased levels of COX-1 protein, but no effect on PGI 2 production was detected (Li et al, 2004). It seems that estrogen increases eNOS protein in cerebral microvessels and decreases cerebrovascular Rho-kinase function, thus improving cerebral microcirculation.…”

“…In vessels from eNOS-knockout mice, estrogen increased levels of COX-1 protein, but no effect on PGI 2 production was detected (Li et al, 2004). Cerebral blood vessels of control mice do not seem to exhibit effects of estrogen on the PGI 2 pathway; however, when NO production is dysfunctional, the impact of estrogen on a COX-sensitive vasodilator is probably revealed.…”