Variant Estrogen and Progesterone Receptor Messages in Human Vascular Smooth Muscle

Hodges, Yvonne K.; Richer, Jennifer K.; Horwitz, Kathryn B.; Horwitz, Lawrence D.

doi:10.1161/01.cir.99.20.2688

Cited by 57 publications

(38 citation statements)

References 32 publications

(36 reference statements)

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“…Progesterone action is mediated via progesterone receptors (PR), which are expressed in arterial and venous smooth muscle cells. 24 However, we previously found that PR expression in mesangial cells is near the limit of detection by reverse transcriptase-polymerase chain reaction (unpublished observation, M. Potier) suggesting that progesterone action and effects are very limited in this vascular bed. Thus, progesterone deficiency may not play an important role in the progression of glomerulosclerosis.…”

Section: Discussionmentioning

confidence: 92%

Estrogen Deficiency Accelerates Progression of Glomerulosclerosis in Susceptible Mice

Elliot¹,

Karl²,

Berho³

et al. 2003

The American Journal of Pathology

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Estrogen deficiency may contribute to the development and progression of glomerulosclerosis in postmenopausal women. The responsiveness to estrogens could be controlled by genetic traits related to those that determine the susceptibility to glomerular scarring. This study was undertaken to determine whether the intensity of the sclerotic response was modified by the estrogen status in sclerosis-prone ROP Os/؉ mice. Ovariectomized ROP Os/؉ mice developed more severe renal dysfunction and glomerulosclerosis than intact, ie, estrogen sufficient agematched female mice. Ovariectomized ROP Os/؉ exhibited increased accumulation of extracellular matrix, predominantly of laminin, and a marked distortion of the glomerular architecture. We found an increase in macrophage infiltration in the mesangium of ovariectomized ROP Os/؉. Estrogen deficiency decreased glomerular estrogen receptor expression in ROP Os/؉ mice, which we had previously found to be low in the parental ROP strain. Thus, although physiological estrogen levels in young ROP Os/؉ mice could not prevent the development of glomerulosclerosis, estrogen deficiency accelerated the progression of glomerular scarring in this mouse strain. This suggests that estrogen replacement will slow but not prevent the progression of glomerulosclerosis. It underscores the importance of the genetic composition of individuals that determines the susceptibility to diseases as well as the response to treatment. Estrogen deficiency may contribute to the development and progression of glomerulosclerosis in postmenopausal women. This is suggested by data from the United States Renal Data System, which show that the female to male ratio of patients with end-stage renal disease because of diabetes increases sharply in the postmenopausal age groups, especially of those from ethnic minorities. 1 The United States Renal Data System data as well as additional genetic and epidemiological studies also suggest that genetic factors play an important role in the susceptibility to develop glomerulosclerosis and the progression to end-stage renal disease. 2,3 The responsiveness to estrogens, which is primarily determined by the level of estrogen receptor (ER) expression, 4 could be controlled by genetic traits related to those that determine the susceptibility to glomerular scarring. We have previously shown that the renal glomerulus is a direct target tissue for estrogens. 5,6 Human and mouse mesangial cells, which play a central role in the pathogenesis of glomerulosclerosis, express both ER subtypes ␣ and ␤. 5 We reported that these ERs were transcriptionally active and that estrogens positively regulated ER expression in mesangial cells. 5 We also found that estrogens provided protection from glomerulosclerosis by regulating genes involved in extracellular matrix (ECM) turnover in a manner leading to the prevention of ECM accumulation in the mesangium. 5,6 Estrogen treatment increased the expression and activity of matrix metalloproteinase (MMP)-9 in mesangial cells isolated from glomeruloscler...

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Section: Discussionmentioning

confidence: 92%

Estrogen Deficiency Accelerates Progression of Glomerulosclerosis in Susceptible Mice

Elliot¹,

Karl²,

Berho³

et al. 2003

The American Journal of Pathology

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“…Progesterone has been recently demonstrated to enhance HLA-G expression in the JEG-3 choriocarcinoma cell line and isolated first-trimester cytotrophoblasts 14 through receptor activation followed by binding to a progesterone response element, which shares 60% homology to the wild-type mouse mammary tumor virus progesterone response element sequence. 15 Furthermore, progesterone receptors are present in human heart as well as vascular endothelial and smooth muscle cells, 24,25 indicating that these tissues are possible targets for progesterone-induced HLA-G expression. Intriguingly, our results show induction of this expression after treatment with progesterone and partial inhibition after coincubation with mifepristone in HCAEC, HAEC, and …”

Section: Discussionmentioning

confidence: 99%

Progesterone Induces Human Leukocyte Antigen-G Expression in Vascular Endothelial and Smooth Muscle Cells

et al. 2008

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Background-Human leukocyte antigen-G (HLA-G) expression in heart transplant patients has been negatively associated with acute cellular rejection and cardiac allograft vasculopathy. We assessed HLA-G expression in vascular human endothelial and smooth muscle cell cultures to determine if future therapeutic agents can be targeted toward inducing HLA-G expression to protect against allograft rejection and vasculopathy. Methods and Results-Human coronary artery endothelial, aortic endothelial, and coronary artery smooth muscle cell cultures were exposed to cytokines (interferon-␥ or interleukin-10), hypoxia/reoxygenation stress, immunosuppressive agents (cyclosporine, sirolimus, or tacrolimus), or progesterone. HLA-G was not expressed by untreated, normoxic cells. Furthermore, maximal doses of interferon-␥, interleukin-10, cyclosporine, sirolimus, or tacrolimus, as well as exposure to hypoxia/reoxygenation, failed to induce HLA-G expression. HLA-G, which has previously not been detected in adult vascular endothelial and smooth muscle cells, was detected by enzyme-linked immunosorbent assay and flow cytometry in human coronary artery endothelial, human coronary aortic endothelial, and human coronary artery smooth muscle cultures after incubation with progesterone in a dose-dependent manner (PϽ0.001) with no change in cellular proliferation ability or viability. This effect was partially blocked in the presence of mifepristone, a progesterone receptor antagonist (human coronary artery endothelial: 48.8Ϯ15.6%; human coronary aortic endothelial: 59.5Ϯ9.5%; human coronary artery smooth muscle: 59.8Ϯ9.8% of control; PϽ0.05). Progesterone-induced HLA-G expression was not protective against hypoxia/reoxygenation injury. Conclusions-HLA-G is not expressed at baseline in vascular endothelial and smooth muscle cells but can be induced by exposure to progesterone. Although tightly regulated, induction of HLA-G expression in these cells may represent a promising and novel therapeutic strategy to protect against rejection and cardiac allograft vasculopathy after heart transplantation.

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“…23 It is also possible that women with abdominal obesity may have functional disturbances in their ERs, or that their arterial tissues express variant forms of ER which may have anomalous transcriptional activities and may inhibit or enhance the effect of wild-type receptors. 24 Hodges et al 24 have recently reported exon deletion variants of ERs in human vascular smooth muscle.…”

Section: Discussionmentioning

confidence: 99%

Expression of estrogen receptors in the coronary arteries of young and premenopausal women in relation to central obesity

Kortelainen

Huttunen

2004

Int J Obes

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OBJECTIVE: To examine the relationship of coronary estrogen receptor (ER) expression with atherosclerotic lesions and central fat accumulation in premenopausal women. SUBJECTS: A total of 52 female forensic autopsy cases aged between 18 and 49 y. METHODS: Height, body weight and waist and hip circumferences were measured and body mass index (BMI) and waist-to-hip ratio (WHR) were calculated. Intima thickness or maximal thickness of the plaque were measured from samples taken from the left anterior descending artery (LAD). Macrophage infiltration and smooth muscle cells were localized by immunostaining. ER was detected immunohistochemically and by Western blot analysis, and the ER immunopositive area in the intima was measured. RESULTS: ER immunoreactivity was observed in the intima in 60% of the samples, and it was most intense in the advanced plaques near the lipid core next to the maximal intensity of macrophage staining. The ER immunopositive area had a significant positive correlation with LAD intima thickness, which in turn was significantly correlated with waist circumference and WHR when adjusted for age and BMI. CONCLUSIONS: Premenopausal women with the central type of fat accumulation have advanced coronary plaques in which ER expression is localized near the lipid-rich and macrophage-rich zone. The higher expression of ER in the arterial plaques may represent a compensatory mechanism against atherosclerosis.

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Variant Estrogen and Progesterone Receptor Messages in Human Vascular Smooth Muscle

Cited by 57 publications

References 32 publications

Estrogen Deficiency Accelerates Progression of Glomerulosclerosis in Susceptible Mice

Estrogen Deficiency Accelerates Progression of Glomerulosclerosis in Susceptible Mice

Progesterone Induces Human Leukocyte Antigen-G Expression in Vascular Endothelial and Smooth Muscle Cells

Expression of estrogen receptors in the coronary arteries of young and premenopausal women in relation to central obesity

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