Thesis

The role of 16α-hydroxyestradiol in pulmonary arterial hypertension

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Awarding institution
  • University of Strathclyde
Date of award
  • 2024
Thesis identifier
  • T17043
Person Identifier (Local)
  • 201990066
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Abstract
  • Pulmonary arterial hypertension (PAH) is a life-limiting disease characterised by progressive remodelling of distal pulmonary arteries. PAH is predominant in females, affecting up to four-fold more women than men. This has led to extensive research into the role of estrogens in PAH. 16α-hydroxyestradiol (16OHE2) is produced during pregnancy. Plasma levels of 16OHE2 are increased in female idiopathic PAH patients, and males and females with portopulmonary PAH. However, its function is undetermined. Many paradoxes have been observed in PAH, and here we provide evidence that the effects of 16OHE2 are also paradoxical. The in vitro effects of 16OHE2 are mainly pathogenic. 16OHE2 increased migration of male and female rat pulmonary artery smooth muscle cells (rPASMCs) but had no effect on proliferation. Mutations in bone morphogenetic protein receptor 2 (BMPR2) account for ~80% of hereditary PAH cases. However, BMPR2 levels are generally reduced in PAH patients regardless of mutation status. 16OHE2 decreased Bmpr2, Smad1, Smad4 and Smad5 mRNA expression in male rPASMCs. Decreased Smad4 expression was attenuated by the estrogen receptor-α antagonist MPP. 16OHE2 also decreased BMPR2 and SMAD4 in human male control (non-PAH) PASMCs. However, 16OHE2 decreased expression of the fibrosis marker Col1a1 in male rPASMCs. 16OHE2 may also mediate pathogenic effects in the aorta. 16OHE2 mediates both pathogenic and protective effects in vivo. 16OHE2 did not induce PAH in male or female C57BL/6 mice but increased right ventricular (RV) hypertrophy in female mice, suggesting that it acts directly on the heart. In lung tissue, 16OHE2 decreased BMPR2 protein levels in female mice but increased pSmad1,5,9 in both sexes. In the RV, 16OHE2 increased protective Id1, Id3 and Sox17 mRNA expression and decreased pathogenic Col1a1 in female mice, and decreased Col3a1 in both sexes. Paradoxical effects may result from peripheral 16OHE2 synthesis (e.g., in lung or adipose) versus exogenous administration.
Advisor / supervisor
  • MacLean, Mandy
Resource Type
DOI

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