Eplerenone Improves Pulmonary Vascular Remodeling And Hypertension By Inhibition Of The Mineralocorticoid Receptor In Endothelial Cells

Pulmonary hypertension is characterized by progressive remodeling of the pulmonary arteries, however, this is not therapeutically targeted yet. Aldosterone and the MR (mineralocorticoid receptor) are key drivers of cardiovascular disease, and there is a growing body of evidence suggesting a role in pulmonary hypertension. Thus, the aim of this study was to investigate the impact of cell type-specific deletion of MR on pulmonary vascular remodeling. To induce pulmonary hypertension, mice were exposed to chronic hypoxia for 6 weeks. Treatment with the MR antagonist eplerenone attenuated pulmonary vascular remodeling, hypertension, and right ventricular dysfunction. In contrast, aldosterone infusion via osmotic minipumps induced pulmonary vascular remodeling. We created 4 different mouse models with cell type-specific MR deletion in smooth muscle cells, endothelial cells, macrophages, or fibroblasts and exposed them to chronic hypoxia. MR deletion from endothelial cells fully recapitulated the beneficial effects of eplerenone while MR deletion from other cell types had no detectable effect on pulmonary vascular remodeling. RNA-seq from isolated MR-deficient and wildtype pulmonary endothelial cells revealed differentially expressed genes as potential downstream mediators of MR related to pulmonary hypertension, including genes related to the endothelin signaling pathway. MR antagonists improve hypoxia-induced pulmonary vascular remodeling via inhibition of MR in endothelial cells but independent from MR in smooth muscle cells, fibroblasts, or macrophages. The results from this study provide the basis for future investigation of potential downstream mediators of MR involved in pulmonary hypertension and further support the clinical evaluation of MR antagonists in pulmonary hypertension.