Funder – American Heart Association
Title – Role of endothelium-derived microvesicles in pulmonary hypertension
Goals – To investigate the role of pulmonary endothelium-derived microvesicles, and their miRNA cargos, in the pathogenesis of pulmonary vascular remodeling and pulmonary hypertension.
In the pulmonary vasculature, the pulmonary vascular endothelial cells (PVEC) and pulmonary artery smooth muscle cells (PASMC) are two key cell types that play a major role in the pathobiology of pulmonary hypertension (PH). As the “signal initiator” in the pulmonary vasculature, PVEC affect the function of PASMC by secreting bioactive agents, myoendothelial injunctions (MEJ) and/or releasing extracellular vesicles (EV) that contain various cargo components including proteins and RNAs etc., under both normal and pathological conditions. So far, our knowledge about the role of endothelial-derived EV and its cargo in the PASMC function and pathogenesis of PH is very limited. In this proposal, we will investigate the role of PVEC-derived microvesicles (MV), especially that of the miRNA cargo in these MV, in the pathogenesis of pulmonary vascular remodeling and PH. In preliminary studies we found that in hypoxia, MV released by mouse PVEC in culture (H-MV) induced mouse PASMC proliferation in vitro and pulmonary vascular remodeling and PH in mice in room air (vs MV released by mouse PVEC in normoxia, H-MV vs N-MV). Using miRNA deep sequencing, we identified 9 miRNAs that were significantly induced in H-MV (v.s. N-MV), including miR-210, a miRNA that is known to induce SMC proliferation and PH. Interestingly, all the other identified miRNAs either suppressed or did not alter SMC proliferation in vitro, including a novel miRNA, miR-212-5p, that had the strongest inhibitory effect on SMC proliferation. We also found that miR-212-5p played a protective role in the pathogenesis of hypoxia-induced PH in mice. Based on these findings, we hypothesize that the endothelium, via MV, promotes vascular remodeling during hypoxia but also provides a break against continued progression of the disease via releasing anti-proliferative miRNAs, such as miR-212, packaged in the MV.