Endocrine Abstracts

Primary arterial hypertension (PAH) is a life-threatening disease that has prevalence of 1 to 2 occurrences per one million individuals. This disease is characterized by excessive proliferation of vascular endothelium and smooth muscle cells, causing thickening the walls of pulmonary arterioles. Recent studies have uncovered a link between familial and idiopathic PAH to BMPRII mutations. The pathology of PAH is characterized by the remodeling of pulmonary arteries due to pulmonary artery smooth muscle cell (PASMC) hyperproliferation. However, the detailed mechanism has yet to be elucidated. Here we investigated the functional link of BMP and vasoactive factors (including endothelin (ET), angiotensin II and aldosterone) in the mitotic actions of PASMCs of PAH lungs. ET1 and aldosterone stimulated PASMC proliferation of idiopathic PAH more efficaciously than that of secondary PAH, whereas angiotensin II and ET3 failed to activate mitosis in either cell type of PASMC. The effects of ET1 and aldosterone were blocked by an ET type-A/B receptor (ETA/BR) antagonist bosentan and a selective MR blocker eplerenone, respectively. BMP-2 and -7 but not BMP-4 and -6 significantly increased cell mitosis in both cell types of PASMCs. Notably, ET1- and aldosterone-induced mitosis as well as MAPK phosphorylation were increased in the presence of BMP-2 and -7 in PASMC isolated from idiopathic PAH, although the additive effects were not observed in PASMC isolated from secondary PAH. Inhibition of ERK suppressed basal, ET1- and aldosterone-induced PASMC mitosis more potently than that of SAPK/JNK inhibition. Given that BMP-2 and -7 upregulated ETA/BR and MR expression and that BMP-2 decreased 11βHSD2 levels in PASMC isolated from idiopathic PAH, BMPR-Smad signaling may play a key role in amplifying the ETA/BR- and/or MR-ERK signaling in PASMCs of PAH lung. The link between BMP and ET and/or MR system may be involved in the progress of PASMC mitosis leading to clinical PAH.