Human uterine and placental arteries exhibit tissue-specific acute responses to 17 -estradiol and estrogen-receptor-specific agonists

Corcoran, Jemma J.; Nicholson, Christopher; Sweeney, Michele; Charnock, Jayne; Robson, Stephen C.; Westwood, Melissa; Taggart, Michael J.

doi:10.1093/molehr/gat095

Cited by 51 publications

(58 citation statements)

References 36 publications

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“…As has been shown for other agonists, estrogen receptor-selective agonists display a marked anatomic heterogeneity in arteries of female rodents, with some vessels responding negligibly while others show rapid relaxation in response to activation of ERs or GPER (Reslan et al, 2013). A similar heterogeneity has recently been reported to be present in human uterine and placental arteries (Corcoran et al, 2013). The implications of such heterogeneity for vascular protection and susceptibility to disease development have been recently discussed (Barton et al, 2013).…”

Section: New Aspects Of Gper Function In the Cardiovascular Systemsupporting

confidence: 82%

Estrogen biology: New insights into GPER function and clinical opportunities

Prossnitz

Barton

2014

Molecular and Cellular Endocrinology

323

267

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Estrogens play an important role in the regulation of normal physiology, aging and many disease states. Although the nuclear estrogen receptors have classically been described to function as ligand-activated transcription factors mediating genomic effects in hormonally regulated tissues, more recent studies reveal that estrogens also mediate rapid signaling events traditionally associated with G protein-coupled receptors. The G protein-coupled estrogen receptor GPER (formerly GPR30) has now become recognized as a major mediator of estrogen’s rapid cellular effects throughout the body. With the discovery of selective synthetic ligands for GPER, both agonists and antagonists, as well as the use of GPER knockout mice, significant advances have been made in our understanding of GPER function at the cellular, tissue and organismal levels. In many instances, the protective/beneficial effects of estrogen are mimicked by selective GPER agonism and are absent or reduced in GPER knockout mice, suggesting an essential or at least parallel role for GPER in the actions of estrogen. In this review, we will discuss recent advances and our current understanding of the role of GPER and certain drugs such as SERMs and SERDs in physiology and disease. We will also highlight novel opportunities for clinical development towards GPER-targeted therapeutics, for molecular imaging, as well as for theranostic approaches and personalized medicine.

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Section: New Aspects Of Gper Function In the Cardiovascular Systemsupporting

confidence: 82%

Estrogen biology: New insights into GPER function and clinical opportunities

Prossnitz

Barton

2014

Molecular and Cellular Endocrinology

323

267

View full text Add to dashboard Cite

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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

247

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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“…While some studies (11,40) have shown intensive immunoreactive signals for both ER␣ and ER␤ in uterine artery tissue sections from latepregnant sheep, another study (69) has suggested that ER␤ may be the main receptor subtype modulated in the uterine artery during gestation. In addition, a study (12) of the uterine circulation in pregnant women has shown that E 2 , PPT, and DPN caused significant relaxation of isolated myometrial arteries with relaxation of E 2 Ͼ DPN Ͼ PPT, whereas G1 did not cause significant relaxation. These observations highlight the importance of further examining ER distribution, activity, and downstream signaling mechanisms in the systemic versus uterine circulation.…”

Section: Er-mediated Inhibition Of Ca 2ϩmentioning

confidence: 99%

Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy

Mata

Reslan

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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RA. Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy. Am J Physiol Heart Circ Physiol 309: H1679 -H1696, 2015. First published September 25, 2015 doi:10.1152/ajpheart.00532.2015.-Normal pregnancy is associated with adaptive hemodynamic, hormonal, and vascular changes, and estrogen (E 2) may promote vasodilation during pregnancy; however, the specific E 2 receptor (ER) subtype, post-ER signaling mechanism, and vascular bed involved are unclear. We tested whether pregnancy-associated vascular adaptations involve changes in the expression/ distribution/activity of distinct ER subtypes in a blood vessel-specific manner. Blood pressure (BP) and plasma E 2 were measured in virgin and pregnant (day 19) rats, and the thoracic aorta, carotid artery, mesenteric artery, and renal artery were isolated for measurements of ER␣, ER␤, and G protein-coupled receptor 30 [G protein-coupled ER (GPER)] expression and tissue distribution in parallel with relaxation responses to E 2 (all ERs) and the specific ER agonist 4,4=,4Љ-(4-propyl-[1H]-pyrazole-1,3,5-triyl)-tris-phenol (PPT; ER␣), diarylpropionitrile (DPN; ER␤), and G1 (GPER). BP was slightly lower and plasma E 2 was higher in pregnant versus virgin rats. Western blots revealed increased ER␣ and ER␤ in the aorta and mesenteric artery and GPER in the aorta of pregnant versus virgin rats. Immunohistochemistry revealed that the increases in ERs were mainly in the intima and media. In phenylephrineprecontracted vessels, E 2 and PPT caused relaxation that was greater in the aorta and mesenteric artery but similar in the carotid and renal artery of pregnant versus virgin rats. DPN-and G1-induced relaxation was greater in the mesenteric and renal artery than in the aorta and carotid artery, and aortic relaxation to G1 was greater in pregnant versus virgin rats. The nitric oxide synthase inhibitor N -nitro-L-arginine methyl ester with or without the cyclooxygenase inhibitor indomethacin with or without the EDHF blocker tetraethylammonium or endothelium removal reduced E 2, PPT, and G1-induced relaxation in the aorta of pregnant rats, suggesting an endothelium-dependent mechanism, but did not affect E 2-, PPT-, DPN-, or G1-induced relaxation in other vessels, suggesting endothelium-independent mechanisms. E 2, PPT, DPN, and G1 caused relaxation of Ca 2ϩ entry-dependent KCl contraction, and the effect of PPT was greater in the mesenteric artery of pregnant versus virgin rats. Thus, during pregnancy, an increase in ER␣ expression in endothelial and vascular smooth muscle layers of the aorta and mesenteric artery is associated with increased ER␣-mediated relaxation via endothelium-derived vasodilators and inhibition of Ca 2ϩ entry into vascular smooth muscle, supporting a role of aortic and mesenteric arterial ER␣ in pregnancyassociated vasodilation. GPER may contribute to aortic relaxation while enhanced ER␤ expression could mediate other genomic vascular effects during pregnancy.

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Human uterine and placental arteries exhibit tissue-specific acute responses to 17 -estradiol and estrogen-receptor-specific agonists

Cited by 51 publications

References 36 publications

Estrogen biology: New insights into GPER function and clinical opportunities

Estrogen biology: New insights into GPER function and clinical opportunities

Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia

Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy

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