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bioRxiv · 10.1101/2023.04.21.537897

Progesterone is an Inducement of Heritable Pulmonary Arterial Hypertension with BMPR2 Mutation

Hu, W.·Zhang, S.-J.·Ding, Y.-J.·Fang, J.·Zhou, L.·Xie, S.·Ge, X.·Fu, L.·Li, Q.-Y.·Qu, J.·Li, S.·Liu, D.
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Abstract

BackgroundBone morphogenetic protein type II receptor (BMPR2) gene mutation accounts for 80% of patients with heritable pulmonary artery hypertension (HPAH), and female mutation carriers have significantly higher penetrance rate than males. The inducement of HPAH penetrance and the mechanism of sex differential penetrance are still elusive. MethodsWe infected or transfected pulmonary artery smooth muscle cells (PASMCs) with shBMPR2 lentivirus or siBMPR2 to simulate the pathologic condition of BMPR2 heterozygous mutation and treated them with progesterone. The HPAH patient-derived induced pluripotent stem cells (iPSCs) were induced into vascular smooth muscle cells (VSMCs) to further verify the cellular phenotype. Wild-type flox+/- female mice and SM22-cre BMPR2 flox+/- female mice (CKO mice) were administered with 1-month progesterone, and their phenotype of PAH was evaluated by right heart catheterization and histopathological examination. ResultsProgesterone promoted the proliferation of PASMCs with BMPR2-knockdownby activating ERK pathway via progesterone receptor (PGR). Activated ERK not only upregulated the phosphorylation and elevation of cMYC, but also induced the transcription of endothelin (EDN1) by promoting the nuclear entry of c-JUN and combination on the its promoter region. Similar results were confirmed by iPSCs-VSMCs experiment. CKO mice developed PAH spontaneously and had increased expression of EDN1, which was further aggravated by exogenous progesterone. ConclusionsProgesterone might be an inducement of HPAH penetrance caused by BMPR2 mutation, accounting for sex differential penetrance.

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Hu, W., Zhang, S.-J., Ding, Y.-J., Fang, J., Zhou, L., Xie, S., Ge, X., Fu, L., Li, Q.-Y., Qu, J., Li, S., Liu, D.. 2023-04-22. Progesterone is an Inducement of Heritable Pulmonary Arterial Hypertension with BMPR2 Mutation. https://doi.org/10.1101/2023.04.21.537897

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