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Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131-5218
The ovarian hormone
17
-estradiol (E2) attenuates chronic hypoxia-induced
pulmonary hypertension. We hypothesized that E2 attenuates this response to hypoxia by decreasing pulmonary expression of the vasoactive and mitogenic peptide endothelin-1 (ET-1). To test
this hypothesis, we measured preproET-1 mRNA and ET-1 peptide levels in
the lungs of adult female normoxic and hypoxic (24 h or 4 wk at
barometric pressure = 380 mmHg) rats with intact ovaries and in
hypoxic ovariectomized (OVX) rats administered E2 or
vehicle via subcutaneous osmotic pumps. Hypoxic exposure increased lung preproET-1 mRNA levels in OVX vehicle-treated rats, but not in rats
with intact ovaries. In addition, E2 replacement
prevented hypoxia-mediated increases in preproET-1 mRNA and ET-1
peptide expression. Considering that hypoxic induction of ET-1 gene
expression is mediated by a hypoxia-inducible transcription factor(s)
(HIF), we further hypothesized that E2-induced
attenuation of pulmonary ET-1 expression during hypoxia results from
decreased HIF activity. We found that E2 abolished
HIF-dependent increases in reporter gene activity. Further experiments
demonstrated that overexpression of the transcriptional coactivator
cAMP response element binding protein (CREB) binding protein
(CBP)/p300, a factor common to both the estrogen receptor and HIF
pathways, eliminated E2-mediated attenuation of
hypoxia-induced ET-1 promoter activity. We conclude that
E2 inhibits hypoxic induction of ET-1 gene expression by interfering with HIF activity, possibly through competition for limiting quantities of CBP/p300.
pulmonary hypertension; hypoxia-inducible factor; reporter gene activity
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