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Open Access Research

BMPR2 expression is suppressed by signaling through the estrogen receptor

Eric D Austin1*, Rizwan Hamid1, Anna R Hemnes2, James E Loyd2, Tom Blackwell2, Chang Yu3, John A Phillips III1, Radhika Gaddipati2, Santhi Gladson2, Everett Gu1, James West2 and Kirk B Lane2

Author Affiliations

1 Department of Pediatrics, Vanderbilt University Medical Center, 1161 21st Ave S Suite DD-2205, Nashville, TN 37232-2578, USA

2 Department of Medicine, Vanderbilt University Medical Center, 1161 21st Ave S Suite DD-2205, Nashville, TN 37232-2578, USA

3 Department of Biostatistics, Vanderbilt University Medical Center, 1161 21st Ave S Suite DD-2205, Nashville, TN 37232-2578, USA

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Biology of Sex Differences 2012, 3:6  doi:10.1186/2042-6410-3-6

Published: 20 February 2012

Abstract

Background

Studies in multiple organ systems have shown cross-talk between signaling through the bone morphogenetic protein receptor type 2 (BMPR2) and estrogen pathways. In humans, pulmonary arterial hypertension (PAH) has a female predominance, and is associated with decreased BMPR2 expression. The goal of this study was to determine if estrogens suppress BMPR2 expression.

Methods

A variety of techniques were utilized across several model platforms to evaluate the relationship between estrogens and BMPR2 gene expression. We used quantitative RT-PCR, gel mobility shift, and luciferase activity assays in human samples, live mice, and cell culture.

Results

BMPR2 expression is reduced in lymphocytes from female patients compared with male patients, and in whole lungs from female mice compared with male mice. There is an evolutionarily conserved estrogen receptor binding site in the BMPR2 promoter, which binds estrogen receptor by gel-shift assay. Increased exogenous estrogen decreases BMPR2 expression in cell culture, particularly when induced to proliferate. Transfection of increasing quantities of estrogen receptor alpha correlates strongly with decreasing expression of BMPR2.

Conclusions

BMPR2 gene expression is reduced in females compared to males in live humans and in mice, likely through direct estrogen receptor alpha binding to the BMPR2 promoter. This reduced BMPR2 expression may contribute to the increased prevalence of PAH in females.

Keywords:
BMPR2; estrogen; hormones; expression; pulmonary hypertension