(4) the distribution and ratio of ERα, ERβ, and GPER in cardiopulmonary tissues and their function, as well as changes in their expression and modifications with age and PAH development; (5) transcriptional programming regulated by ERα, ERβ, or/and GPER as well as estrogen metabolites; (6) the bi-directional relationship between estrogen signaling and the presence/progression of disease including elucidating any potential positive or negative feedback loops. The gene discussed is ESR1; the disease is pulmonary arterial hypertension.