Estrogen Induces Vascular Wall Dilation

Abstract

Estrogen has been shown to affect vascular cell and arterial function in vitro and in vivo. Here we examined the ability of estradiol (E 2) to cause rapid arterial dila-tion of elastic and muscular arteries in vivo and the mechanisms involved. E 2 administration caused a rapid increase in the outer wall diameter of both types of arteries in ovariectomized female mice. This resulted from estrogen receptor (ER)-mediated stimulation of ni-tric oxide production, demonstrated by preinjecting the mice arteries with a soluble inhibitor of nitric oxide (monomethyl L-arginine) and by showing the absence of E 2 action in eNOS؊/؊ mice. Rapid activation of both ERK/MAP kinase and phosphatidylinositol 3-kinase ac-tivity was found in the E 2 -exposed arteries, and inhibit-ing either kinase prevented the vasodilatory action of E 2 . Kinase activation and vasodilator responses to E 2 were absent in either ER␣ or ER␤ knock-out mice, im-plicating both receptor subtypes as mediating this E 2 action. These results indicate that E 2 modulation of ar-terial tonus through plasma membrane ER and rapid signaling could underlie many previously observed ac-tions of estrogen reported to occur in women. Estrogen has been suggested to modulate vascular physiol-ogy and function from a variety of studies in cellular, animal, and human models. Administration of sublingual estradiol to women significantly reduces exercise-induced myocardial is-chemia (1). This perhaps is related to estradiol (E 2) 1 binding the estrogen receptor (ER) and stimulating nitric oxide (NO) production (2). Genetic deletion of ER␤ results in the develop-ment of hypertension in middle aged female and male mice (3), possibly from the loss of E 2 -induced NO, resulting in endothe-lial dysfunction and oxidative stress (4). Relevant to this pro-posed model, E 2 rescues rodents from ischemia-reperfusion injury of their small arteries in muscle, via signaling to NO (5). E 2 decreases myocardial infarct size, prevents ventricular ar-rhythmia, and preserves cell structure in ischemia-reperfusion injury of the heart in animal models (6). E 2 also decreases myocardial infarct size and prevents ventricular arrhythmia in women (7, 8). In some instances these effects of E 2 are non-genomic, hypothetically resulting from rapid signaling by E 2 (9). In contrast, conjugated estrogen plus medroxyprogesterone does not prevent the occurrence of primary or secondary arte-riosclerotic heart disease (10, 11). This indicates that estrogen may modulate discrete aspects of cardiovascular tone and func-tion, unrelated to the pathogenesis of atherosclerosis. One potentially important action of estrogen is to induce arterial dilation. Vasodilation opposes excessive vasoconstric-tion that results in decreased blood flow and increased systemic vascular resistance. How might E 2 rapidly induce dilation of the arterial wall? This is likely to occur through binding vas-cular cell receptors, because ER␣ and ER␤ are present in vascular endothelial and smooth muscle cells (12, 13). Tradi-tionally, it is felt that steroid sex hormones act in cells after binding their nuclear receptors (14). The steroid-receptor com-plex then binds specific response elements in the 5Ј promoter region of target genes. Gene transactivation may also result from more complex protein-protein interactions between the ER, transcription factors such as AP-1, co-activators such as SRC-1, and the basal transcriptional machinery proteins. Additionally, there is evidence for plasma membrane-local-ized ER that rapidly signal through G proteins to discrete cell biological functions (reviewed in Ref. 15). In vitro, E 2 rapidly stimulates the release of prolactin (16), cAMP (17), and triggers a calcium spike in seconds (18). E 2 activates signal cascades that culminate in the activation of ERK, a member of the MAP kinase family (19). E 2 preserves neurons from in vitro insults that cause apoptosis or necrosis via signaling through ERK activation (20). Also, E 2 rapidly activates NO synthase activity via ERK or PI3K and membrane ER in endothelial cells (EC) (21, 22). The sex steroid prevents the vascular smooth muscle response in rodents to acute vascular injury (angioplasty), pre-venting the closure of the vessel lumen (23). We showed previ-ously in vitro that E 2 stimulates a p38 MAP kinase-MAPKAP-2 and heat shock protein 27 cascade, leading to EC survival and the formation of primitive capillary tubes (9). Here we investigated the ability of intra-arterial E 2 and its mechanism to effect rapid vascular dilation. We found that the sex steroid acts in both elastic and muscular arteries and causes vasodilation through rapid signal transduction to NO generation. These effects were mediated by both the ER␣ and ER␤ receptors and were likely the result of membrane ER action.