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.
"The association of BK Ca channels with, and their regulation by, GPCRs has been well established in other tissues. For example, M2 muscarinic receptors inhibit BK Ca currents in tracheal SMCs (Zhou et al., 2008), whereas the G protein-coupled estrogen receptor 1 stimulates BK Ca activity in coronary SMCs (Yu et al., 2011). Here we discuss five GPCRs that have been linked to uterine function: oxytocin, prostaglandin F 2α , corticotropin-releasing hormone, nociceptin, and melatonin receptors. "
[Show abstract][Hide abstract] ABSTRACT: The large-conductance voltage- and Ca(2+)-activated K(+) channel (BKCa) is an important regulator of membrane excitability in a wide variety of cells and tissues. In myometrial smooth muscle, activation of BKCa plays essential roles in buffering contractility to maintain uterine quiescence during pregnancy and in the transition to a more contractile state at the onset of labor. Multiple mechanisms of modulation have been described to alter BKCa channel activity, expression, and cellular localization. In the myometrium, BKCa is regulated by alternative splicing, protein targeting to the plasma membrane, compartmentation in membrane microdomains, and posttranslational modifications. In addition, interaction with auxiliary proteins (i.e., β1- and β2-subunits), association with G-protein coupled receptor signaling pathways, such as those activated by adrenergic and oxytocin receptors, and hormonal regulation provide further mechanisms of variable modulation of BKCa channel function in myometrial smooth muscle. Here, we provide an overview of these mechanisms of BKCa channel modulation and provide a context for them in relation to myometrial function.
Frontiers in Physiology 07/2014; 5:289. DOI:10.3389/fphys.2014.00289 · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The renin-angiotensin-aldosterone (RAA) system is markedly activated in pregnancy. We evaluated if mineralocorticoid receptors (MR), a major component of the RAA system, are involved in the reduced vascular reactivity associated with pregnancy. Canrenoate (MR antagonist; 20 mg·kg(-1)·day(-1)) was administered to nonpregnant (NP) rats for 7 days and to pregnant rats from day 15 to 22 of gestation. These were killed on day 17, 19, or 22 of gestation and, for NP rats, after 7 days treatment. Constrictor responses to phenylephrine (PhE) and KCl were measured in endothelium-denuded thoracic aortic rings under the influence of modulators of potassium (activators) and calcium (blocker) channels. Responses to the constrictors were blunted from days 17 to 22 of gestation. Although canrenoate increased responses to PhE and KCl, it did not reverse their blunted responses in gestation. NS-1619 and cromakalim (respectively, high-conductance calcium-activated potassium channels and ATP-sensitive potassium channel activators) diminished responses to both PhE and KCl. Inhibition by NS-1619 on responses to both agonists was decreased under canrenoate treatment in NP, but the reduced influence of NS-1619 during gestation was reversed by the mineralocorticoid antagonist. Cromakalim reduced the response to PhE significantly in the pregnant groups; this effect was enhanced by canrenoate. Finally, nifedipine (calcium channel blocker) markedly reduced KCl responses but to a lesser extent at the end of pregnancy, an inhibiting effect that was increased with canrenoate treatment. These data demonstrate that treating rats with a MR antagonist increased vascular reactivity but that it differentially affected potassium and calcium channel activity in aortas of NP and pregnant animals. This suggests that aldosterone is one of the components involved in vascular adaptations to pregnancy.
[Show abstract][Hide abstract] ABSTRACT: Estrogen is a potent steroid with pleiotropic effects, which have yet to be fully elucidated. Estrogen has both nuclear and non-nuclear effects. The rapid response to estrogen, which involves a membrane associated estrogen receptor(ER) and is protective, involves signaling through PI3K, Akt, and ERK 1/2. The nuclear response is much slower, as the ER-estrogen complex moves to the nucleus, where it functions as a transcription factor, both activating and repressing gene expression. Several different ERs regulate the specificity of response to estrogen, and appear to have specific effects in cardiac remodeling and the response to injury. However, much remains to be understood about the selectivity of these receptors and their specific effects on gene expression. Basic studies have demonstrated that estrogen treatment prevents apoptosis and necrosis of cardiac and endothelial cells. Estrogen also attenuates pathologic cardiac hypertrophy. Estrogen may have great benefit in aging as an anti-inflammatory agent. However, clinical investigations of estrogen have had mixed results, and not shown the clear-cut benefit of more basic investigations. This can be explained in part by differences in study design: in basic studies estrogen treatment was used immediately or shortly after ovariectomy, while in some key clinical trials, estrogen was given years after menopause. Further basic research into the underlying molecular mechanisms of estrogen's actions is essential to provide a better comprehension of the many properties of this powerful hormone.
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