Human umbilical vascular endothelial cells express estrogen receptor beta (ERβ) and progesterone receptor A (PR-A), but not ERα and PR-B

Tóth, Bettina; Saadat, Gitti; Geller, Alrun; Scholz, Christoph; Schulze, Sandra; Friese, Klaus; Jeschke, Udo

doi:10.1007/s00418-008-0426-7

Cited by 42 publications

(29 citation statements)

References 22 publications

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“…The nPR antibody used in this study does not distinguish between PR-A and PR-B proteins because it was generated to an amino acid sequence in the COOH-terminal of the receptor. The immunoreactive protein detected by the antibody most likely is PR-A, because only this nPR subtype was detected in HUVECs using nPR subtypespecific antibodies (67). The finding that a third distinct receptor involved in progesterone signaling, PGRMC1, is also ex- …”

Section: E907mentioning

confidence: 96%

Progesterone increases nitric oxide synthesis in human vascular endothelial cells through activation of membrane progesterone receptor-α

Pang

Dong

Thomas

2015

American Journal of Physiology-Endocrinology and Metabolism

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Pang Y, Dong J, Thomas P. Progesterone increases nitric oxide synthesis in human vascular endothelial cells through activation of membrane progesterone receptor-␣. Am J Physiol Endocrinol Metab 308: E899 -E911, 2015. First published March 24, 2015; doi:10.1152/ajpendo.00527.2014.-Progesterone exerts beneficial effects on the human cardiovascular system by inducing rapid increases in nitric oxide (NO) production in vascular endothelial cells, but the receptors mediating these nongenomic progesterone actions remain unclear. Using human umbilical vein endothelial cells (HUVECs) as a model, we show that progesterone binds to plasma membranes of HUVECs with the characteristics of membrane progesterone receptors (mPRs). The selective mPR agonist Org OD 02-0 had high binding affinity for the progesterone receptor on HUVEC membranes, whereas nuclear PR (nPR) agonists R5020 and medroxyprogesterone acetate displayed low binding affinities. Immunocytochemical and Western blot analyses confirmed that mPRs are expressed in HUVECs and are localized on their plasma membranes. NO levels increased rapidly after treatment with 20 nM progesterone, Org OD 02-0, and a progesterone-BSA conjugate but not with R5020, suggesting that this progesterone action is at the cell surface and initiated through mPRs. Progesterone and Org OD 02-0 (20 nM) also significantly increased endothelial nitric oxide synthase (eNOS) activity and eNOS phosphorylation. Knockdown of mPR␣ expression by treatment with small-interfering RNA (siRNA) blocked the stimulatory effects of 20 nM progesterone on NO production and eNOS phosphorylation, whereas knockdown of nPR was ineffective. Treatment with PI3K/ Akt and MAP kinase inhibitors blocked the stimulatory effects of progesterone, Org OD 02-0, and progesterone-BSA on NO production and eNOS phosphorylation and also prevented progesterone-and Org OD 02-0-induced increases in Akt and ERK phosphorylation. The results suggest that progesterone stimulation of NO production in HUVECs is mediated by mPR␣ and involves signaling through PI3K/Akt and MAP kinase pathways. membrane progesterone receptors; human vascular endothelial cells; rapid progesterone action; nitric oxide; nitric oxide synthase FEMALE REPRODUCTIVE HORMONES are widely considered to have beneficial effects on cardiovascular functions in women. The lower incidence of cardiovascular disease in middle-aged premenopausal women than in men and postmenopausal women has been attributed to the presence of female sex steroids in the circulation (22,27,41,47). Blood pressure is typically lower in women than in men and often drops during pregnancy when circulating levels of estrogens and progesterone are elevated (30,70,71). Furthermore, synthesis of a major regulator of vasodilation, nitric oxide (NO), is greater in women than in men (14). These sex differences in the occurrence of cardiovascular disease are due partly to the well-known beneficial effects of estrogens, which include upregulation of NO production in human endothelial cells (7,18,28,33). Numerous...

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Section: E907mentioning

confidence: 96%

Progesterone increases nitric oxide synthesis in human vascular endothelial cells through activation of membrane progesterone receptor-α

Pang

Dong

Thomas

2015

American Journal of Physiology-Endocrinology and Metabolism

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“…P4 regulates the secretion of plasminogen activator [18] and endothelin-1 [19] by aortic endothelial cells in cows. Additionally, P4 has been shown to induce prostacyclin production from human umbilical vein endothelial cells (HUVEC) by enhancing cyclooxygenase (COX)-1 and COX-2 expression [20] and to up-regulate PR expression [21]. These studies suggest that PR expressed in the endothelial cells of the bovine CL is as functional as PR expressed in bovine aorta and the human umbilical vein and that P4 secreted from both large and small luteal cells plays a role in regulating endothelial cell function in the bovine CL.…”

Section: Discussionmentioning

confidence: 99%

Changes in the Levels of Progesterone Receptor mRNA and Protein in the Bovine Corpus Luteum During the Estrous Cycle

Sakumoto

Vermehren²,

Kenngott³

et al. 2010

Journal of Reproduction and Development

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Abstract. Progesterone (P4) is synthesized in the luteal cells of many species. The objective of the present study was to determine the expression pattern of P4 receptor (PR) mRNA and the distribution of PR protein in the bovine corpus luteum (CL) during the estrous cycle. The gene expression of PR in the bovine CL throughout the estrous cycle was determined by real-time PCR analysis, and the PR protein expression was evaluated by immunohistochemistry. Messenger RNA of PR was clearly expressed in the CL throughout the estrous cycle. The level of PR mRNA in the CL was highest at the early stage of the estrous cycle and was higher at the mid and late stages than at the regressed stage (P<0.01). In regard to the distribution of PR, the protein was expressed in both small and large luteal cells and in vascular endothelial cells throughout the estrous cycle. These results suggest that P4 has a role in regulating luteal and endothelial cell function in the bovine CL, especially at the early luteal stage as an autocrine/paracrine regulator. Key words: Corpus luteum, Cows, Immunohistochemistry, Progesterone, Receptor (J. Reprod. Dev. 56: [219][220][221][222] 2010) rogesterone (P4), which is synthesized in luteal cells, is a steroid hormone that is essential for establishment of pregnancy in a variety of species [1]. P4 mediates its effect through an intracellular receptor, the P4 receptor (PR), and the interaction of P4 and PR in target tissues has various physiological effects. P4 is known to regulate not only endometrial morphology but also corpus luteum (CL) function in a variety of species. Recent studies have demonstrated that Fas-and cytokine-mediated apoptosis is suppressed by P4 in the bovine CL [2,3]. In addition, the number of luteinizing hormone (LH) receptors per cell is increased by treatment with P4 using cultured bovine luteal cells [4]. These findings lead us to hypothesize that PR regulates bovine CL function in an autocrine or paracrine manner. The bovine CL consists of a variety of cell types including large and small luteal cells, endothelial cells and fibroblasts, each of which has a different function [5]. Large luteal cells, which are luteinized from granulosa cells, are the major source of P4 in the bovine CL, but small luteal cells, which are luteinized from theca cells, produce P4 in response to LH with high sensitivity [1]. In the present study, to determine which cell types express PR, we measured the distribution of PR in the bovine CL by immunohistochemistry. Expression of PR mRNA in the bovine CL from different stages of the estrous cycle was also studied using real-time PCR. Materials and Methods Collection of the bovine corpus luteumOvaries containing CLs from German Fleckvieh cows were collected at a local abattoir within 10-30 min after exsanguination. The luteal stage was classified as early (days 2-4 after ovulation), mid (days 8-11), late (days 14-16) or regressed (days 19-21) by macroscopic observation of the ovary as described previously (n= 5/stage) [6]. For gene expression st...

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“…Recently, basic findings on the expression of estrogen receptor (ER) and PR in HUVECs were published, indicating the lack of ER ␣ and PR-B expression in HUVECs [25] .…”

Section: Discussionmentioning

confidence: 99%

“…In brief, HUVECs were cultivated under sterile conditions in chamber slide cultures Quadriperm (Nunc) for up to 72 h, dried, wrapped and stored at -80 ° C as described earlier [25] . After thawing, cells were briefly fixed with formalin (Merck; 5% in PBS, 5 min).…”

Section: Immunocytochemistrymentioning

confidence: 99%

Effects of Progesterone and Its Antagonist Mifepristone on Progesterone Receptor A Expression in Human Umbilical Vein Endothelial Cells

Tóth¹,

Scholz

Ochsenkühn³

et al. 2009

Gynecol Obstet Invest

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Effects of female steroid hormones on endothelial cells are gaining increased importance due to several studies on the effects of hormonal treatment on cardiovascular risk. Recent data argue for an improvement of endothelium-derived relaxation and impaired vascular contraction by estradiol, whereas progesterone and testosterone might entail contrary effects. So far, gestagenic influence on endothelial cell physiology is poorly understood. Human umbilical vein endothelial cells (HUVECs) exposed to the female sex hormones estradiol and progesterone show expression of estrogen receptor-β (ERβ) and progesterone receptor A (PR-A), and are negative for ERα and PR-B. The aim of this study was to analyze the expression and stimulation of PR-A and -B in HUVECs after stimulation with progesterone and PR antagonists that are commercially available. PR-B expression or upregulation was abrogated after application of progesterone or antagonists to HUVECs. Expression of PR-A could be significantly upregulated with progesterone and mifepristone. Unexpectedly, stimulation with the progesterone antagonist RU486 (mifepristone) was accomplished by an upregulation of PR-A expression in our study. We conclude that gestagenic effects on HUVECs independent of modulators are mediated via the PR-A.

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Human umbilical vascular endothelial cells express estrogen receptor beta (ERβ) and progesterone receptor A (PR-A), but not ERα and PR-B

Cited by 42 publications

References 22 publications

Progesterone increases nitric oxide synthesis in human vascular endothelial cells through activation of membrane progesterone receptor-α

Progesterone increases nitric oxide synthesis in human vascular endothelial cells through activation of membrane progesterone receptor-α

Changes in the Levels of Progesterone Receptor mRNA and Protein in the Bovine Corpus Luteum During the Estrous Cycle

Effects of Progesterone and Its Antagonist Mifepristone on Progesterone Receptor A Expression in Human Umbilical Vein Endothelial Cells

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