Estrogen Oppositely Regulates Pulmonary Hypertension via METTL3/PFKFB3 under Normoxia and Hypoxia

Despite extensive investigation into estrogen's role in pulmonary hypertension (PH) development, its effects, whether beneficial or detrimental, remain contentious. This study aimed to elucidate estrogen's potential role in PH under normoxic and hypoxic conditions. Using norfenfluramine- and hypoxia-induced rat models of PH, the study evaluated the impact of 17β-estradiol (E2) on PH progression. E2 promoted PH development under normoxia while providing protection under hypoxia. Mechanistically, under normoxia, E2 upregulated METTL3 (methyltransferase-like 3) gene transcription and protein via an estrogen response element-dependent pathway, which in turn increased the N6-methyladenosine methylation and translational efficiency of PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3) mRNA, leading to increased PFKFB3 protein levels and enhanced proliferation and migration of pulmonary artery smooth muscle cells. Conversely, under hypoxia, E2 downregulated METTL3 transcription through a hypoxia response element-dependent mechanism driven by increased HIF-1α (hypoxia-inducible factor 1α) levels, resulting in reduced PFKFB3 protein expression and diminished pulmonary artery smooth muscle cell proliferation and migration. METTL3 and PFKFB3 proteins are upregulated in the pulmonary arteries of patients with pulmonary arterial hypertension. Collectively, these findings suggest that E2 exerts differential effects on PH progression via dual regulation of the METTL3/PFKFB3 protein under normoxic and hypoxic conditions, positioning the METTL3/PFKFB3 protein as a potential therapeutic target for PH treatment.