Estrogens can either relax or contract arteries via rapid, nongenomic mechanisms involving classic estrogen receptors (ER). In addition to ERα and ERβ, estrogen may also stimulate G protein-coupled estrogen receptor 1 (GPER) in nonvascular tissue; however, a potential role for GPER in coronary arteries is unclear. The purpose of this study was to determine how GPER activity influenced coronary artery reactivity. In vitro isometric force recordings were performed on endothelium-denuded porcine arteries. These studies were augmented by RT-PCR and single-cell patch-clamp experiments. RT-PCR and immunoblot studies confirmed expression of GPER mRNA and protein, respectively, in smooth muscle from either porcine or human coronary arteries. G-1, a selective GPER agonist, produced a concentration-dependent relaxation of endothelium-denuded porcine coronary arteries in vitro. This response was attenuated by G15, a GPER-selective antagonist, or by inhibiting large-conductance calcium-activated potassium (BK(Ca)) channels with iberiotoxin, but not by inhibiting NO signaling. Last, single-channel patch-clamp studies demonstrated that G-1 stimulates BK(Ca) channel activity in intact smooth muscle cells from either porcine or human coronary arteries but had no effect on channels isolated in excised membrane patches. In summary, GPER activation relaxes coronary artery smooth muscle by increasing potassium efflux via BK(Ca) channels and requires an intact cellular signaling mechanism. This novel action of estrogen-like compounds may help clarify some of the controversy surrounding the vascular effects of estrogens.

Historically, the vasodilatory prostanoids, especially prostacyclin and prostaglandin E(2), are believed to contribute significantly to the regulation of normal vascular tone and blood pressure (BP), primarily by counteracting the prevailing effects of the systemic vasoconstrictor systems, including angiotensin II, the catecholamines, and vasopressin. In contrast, the primary vasoconstrictor prostanoid thromboxane A(2) (TxA(2)) is produced in far smaller quantities in the normal state. While TxA(2) is believed to play a significant role in a variety of cardiovascular diseases, such as myocardial infarction, cerebral vasospasm, hypertension, preeclampsia, and various thrombotic disorders, its role in the regulation of vascular tone and BP in the normal physiological state is, at best, uncertain. Numerous studies have firmly established the dogma that TxA(2), while important in pathophysiological states in males, plays little or no role in the regulation of vascular tone or BP in females, except in the pulmonary vasculature. However, this concept is largely based on the predominant and preferential use of males in animal and human studies. Recent studies from our laboratory and others challenge this dogma and reveal that the TxA(2) pathway in the systemic vascular wall is an estrogen-dependent mechanism that appears to play an important role in the regulation of vascular tone and BP in females, in both normal and pathophysiological states. It is proposed that the potent vasoconstrictor action of TxA(2) is beneficial in the female in the normal state by acting as a local counterregulatory mechanism to increase vascular tone and BP and defend against hypotension that could result from the multiple estrogen-sensitive local vasodilator mechanisms present in the female vascular wall. Validation of this proposal must await further studies at the systemic, tissue, and molecular levels.

Recent studies reveal that testosterone (TES) produces rapid vasorelaxation of mesenteric arterioles at physiological concentrations; however, little is known about TES mechanisms in vascular smooth muscle (VSM). Therefore, acute mechanisms of TES were examined in endothelium‐intact rings of mesenteric arterioles (MA, 200 μm, dia.) prepared from male Sprague‐Dawley (SD) and Testicular‐feminized (Tfm; androgen receptor‐deficient) rats (14–18 wks age) for isometric tension using Halpern‐Mulvany myography. MA were precontracted with phenylephrine (20 μM) and a concen.‐response to TES was obtained (0.1–300 nM). Data are means+S.E (N = 3–13 rats). TES produced vasorelaxation at physiological concentrations in SD (50 ± 7%, EC50 = 2.3 ± 0.5 nM) and in Tfm (38 ± 5%, EC50 = 1.5 ± 0.5 nM). Pretreatment of Tfm MA with the neuronal NOS inhibitor LNPA (10 μM) nearly abolished TES effects (5.5 ± 3.8%). In SD VSM cells, TES activated the fluorescent nitric oxide (NO) indicator DAF‐2DA, while LNPA (10 μM) eliminated this effect of TES. These data suggest that: 1) TES exerts rapid vasorelaxing effects on VSM primarily through activation of nNOS and nitric oxide production; 2) TES‐induced vasorelaxation is a direct, nongenomic effect on VSM, independent of the cytosolic androgen receptor. (NIH: HL‐080402)

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Previously, we reported that estrogen receptors (ERα, ERβ) exert differing effects on mesenteric arterial reactivity to vasopressin (VP) and that estrogen enhances constrictor prostanoids by upregulating thromboxane synthase and cyclooxygenase‐2 message in rat aorta. We measured mean arterial blood pressure (BP), thromboxane (TXA2) and prostacyclin (PGI2) release by mesenteric arterioles (200 μm) in normo‐ and aortic coarctation‐induced hypertensive (NT and HT) Sprague‐Dawley female rats that were intact (INT), ovariectomized (OvX), or OvX + treated with ER‐selective agonists DPN (ERβ) or PPT (ERα), 100μg/rat/day (13–15 days). BP in PPT HT (180±4 mmHg) is similar to INT HT (183±4) and DPN HT (182±4). BP is lowest in OVX HT (153±3). BP in NT did not differ (mean = 127±1). Basal TXA2 was lowest in OVX and DPN NT (51 ± 20; 40 ± 7 pg/mg tissue/45 min), while INT or PPT NT are higher (93 ± 1; 93 ± 10). HT increases basal TXA2 threefold. VP (10−8) increases TXA2 least in DPN NT (79 ± 11) vs INT NT (108 ± 1), OVX NT (137 ± 33) or PPT NT (134 ± 31). HT increases VP stimulated TXA2. PPT HT increased the most (643 ± 137) vs INT HT (415 ± 46), OVX HT (277 ± 56) or DPN HT (334 ± 33). PGI2 shows similar trends in all groups; PPT enhanced basal and VP stimulated PGI2 the most. These data suggest that ERα enhances TXA2 and PGI2 to a greater extent than ERβ. The increased PGI2 does not afford protection to BP in PPT HT. (Supported by NIH: HL‐080402)