Pregnancy Augments G Protein Estrogen Receptor (GPER) Induced Vasodilation in Rat Uterine Arteries via the Nitric Oxide - cGMP Signaling Pathway

Tropea, Teresa; Francesco, Ernestina Marianna De; Rigiracciolo, Damiano Cosimo; Maggiolini, Marcello; Wareing, Mark; Osol, George; Mandalà, Maurizio

doi:10.1371/journal.pone.0141997

Cited by 56 publications

(53 citation statements)

References 35 publications

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“…Interestingly, the copper-chelating agent TEPA exerted an inhibitory action on the activation of the aforementioned pathway (90), in accordance with previous studies demonstrating that copper-chelating agents can exert anti-tumor effects (91). Altogether, these results indicate that diverse stimuli including hypoxia may trigger relevant biological responses through GPER, which was recently shown to be also involved in the stimulatory effects exerted by aldosterone in breast cancer cells and breast tumor-derived endothelial cells (92) as well as in pregnancy-induced vasodilation of rat uterine arteries (93).…”

Section: Gper Is Involved In Hypoxia-mediated Signalingsupporting

confidence: 89%

Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling

Lappano

Rigiracciolo

Marco

et al. 2016

AAPS J

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Abstract. G protein-coupled receptors (GPCRs) are cell surface proteins mainly involved in signal transmission; however, they play a role also in several pathophysiological conditions. Chemically heterogeneous molecules like peptides, hormones, lipids, and neurotransmitters activate second messengers and induce several biological responses by binding to these seven transmembrane receptors, which are coupled to heterotrimeric G proteins. Recently, additional molecular mechanisms have been involved in GPCR-mediated signaling, leading to an intricate network of transduction pathways. In this regard, it should be mentioned that diverse GPCR family members contribute to the adaptive cell responses to low oxygen tension, which is a distinguishing feature of several illnesses like neoplastic and cardiovascular diseases. For instance, the G protein estrogen receptor, namely G protein estrogen receptor (GPER)/GPR30, has been shown to contribute to relevant biological effects induced by hypoxia via the hypoxia-inducible factor (HIF)-1α in diverse cell contexts, including cancer. Likewise, GPER has been found to modulate the biological outcome of hypoxic/ischemic stress in both cardiovascular and central nervous systems. Here, we describe the role exerted by GPCR-mediated signaling in low oxygen conditions, discussing, in particular, the involvement of GPER by a hypoxic microenvironment.

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Section: Gper Is Involved In Hypoxia-mediated Signalingsupporting

confidence: 89%

Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling

Lappano

Rigiracciolo

Marco

et al. 2016

AAPS J

Self Cite

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“…This third ER type may serve an important role in the regulation of muscle tone, works solely through non-genomic pathways, and also stimulates NO and cGMP production in various cell types, including SMCs (51,53,54). In addition to the activation of ERα, PPT has also been demonstrated to activate GPR30 in a range of contexts, particularly when used in a high dose range (55).…”

Section: Discussionmentioning

confidence: 99%

Estrogen relaxes gastric muscle cells via a nitric oxide‑ and cyclic guanosine monophosphate‑dependent mechanism: A sex‑associated differential effect

et al. 2018

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Various gastrointestinal (GI) disorders have a higher prevalence in women than in men. In addition, estrogen has been demonstrated to have an inhibitory effect on the contractility of GI smooth muscle. Although increased plasma estrogen levels have been implicated in GI disorders, the role of gastric estrogen receptor (ER) in these sex-specific differences remains to be fully elucidated. The present study was designed to investigate the sex-associated differences in the expression of the two ER isoforms, ERα and ERβ, and the effect of estrogen on gastric muscle contraction via the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway. Experiments were performed on single gastric smooth muscle cells (GSMCs) isolated from male and female Sprague Dawley rats. The effect of acetylcholine (ACh), a muscarinic agonist, on the contraction of GSMCs was measured via scanning micrometry in the presence or absence of 1 µM 17β-estradiol (E2), an agonist to the majority of ERs, 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT), an ERα agonist, or diarylpropionitrile (DPN), an ERβ agonist. The protein expression levels of ER subtypes in GSMCs were measured using a specifically designed ELISA. GSMCs from female rats had a higher expression of ERα and ERβ protein compared with GSMCs from males. ACh induced less contraction in female that in male GSMCs. Pre-treatment of GSMCs with E2 reduced the contraction of GSMCs from both sexes, but to a greater extent in those from females. PPT and DPN inhibited ACh-induced contraction in GSMCs from females. Furthermore, E2 increased NO and cGMP levels in GSMCs from males and females; however, higher levels were measured in females. Of note, pre-incubation of female GSMCs with Nω-nitro-L-arginine, a NO synthase inhibitor, or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a guanylyl cyclase inhibitor, reduced the inhibitory effect of estrogen on GSMC contraction. In conclusion, estrogen relaxes GSMCs via an NO/cGMP-dependent mechanism, and the reduced contraction in GSMCs from females by estrogen may be associated with the sex-associated increased expression of ERα and ERβ, and greater production of NO and cGMP, compared with that in GSMCs from males.

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“…In the rat uterus, GPR30 has been implicated in estrogen-mediated reduction in vascular tone (Tropea et al 2015) but some have suggested this may not be the case in humans (Corcoran et al 2014). Others still have shown a role for GPR30 in regulation of vascular tone in human mammary arteries (Haas et al 2009).…”

Section: Hormonal Control Of Vascular Adaptationmentioning

confidence: 99%

Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia

Boeldt

Bird

2017

Journal of Endocrinology

257

152

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Maternal vascular adaptation to pregnancy is critically important in order to expand the capacity for blood flow through the uteroplacental unit to meet the needs of the developing fetus. Failure of the maternal vasculature to properly adapt can result in hypertensive disorders of pregnancy such as preeclampsia (PE). Herein, we review the endocrinology of maternal adaptation to pregnancy and contrast this with that of PE. Our focus is specifically on those hormones with directly impact endothelial cell function and dysfunction, as endothelial cell dysfunction is a hallmark of PE. A variety of growth factors and cytokines are present in normal vascular adaptation to pregnancy but have also been shown to be circulating at abnormal levels in PE pregnancies. Many of these factors promote endothelial dysfunction when present at abnormal levels by acutely inhibiting key Ca2+ signaling events and chronically promoting the breakdown of endothelial cell-cell contacts. Increasingly, our understanding of how the contributions of the placenta, immune cells, and the endothelium itself promote the endocrine milieu of PE is becoming more clear. We then describe in detail how the complex endocrine environment of PE effects endothelial cell function, why this has contributed to the difficulty in fully understanding and treating this disorder, and how a focus on signaling convergence points of many hormones may be a more successful treatment strategy.

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Pregnancy Augments G Protein Estrogen Receptor (GPER) Induced Vasodilation in Rat Uterine Arteries via the Nitric Oxide - cGMP Signaling Pathway

Cited by 56 publications

References 35 publications

Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling

Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling

Estrogen relaxes gastric muscle cells via a nitric oxide‑ and cyclic guanosine monophosphate‑dependent mechanism: A sex‑associated differential effect

Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia

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