Funder – Gilead
Title – A protective role of miR-212-5p in pulmonary hypertension
Goals – To investigate the role of miR-212 in pulmonary vascular smooth muscle and endothelial cells, and the transfer of miR-212 from endothelium to smooth muscle cells.
Pulmonary hypertension (PH) is a devastating disease that results in a progressive increase in pulmonary vascular resistance, right ventricular failure, and ultimately death of patients. The endothelial and smooth muscle cells (EC and SMC) are two key cell types in the pulmonary vasculature. Crosstalk, like paracrine effects, between these two cell types plays an important role in maintaining the normal conditions of the vasculature and the pathogenesis of PH. However, the role of extracellular vesicle transfer between the two cell types and the exact mechanisms involved in the pathogenesis of PH are not well understood.
We found that under hypoxia, pulmonary artery EC (PAEC) release extracellular vesicles, specifically microvesicles (MV), that induce PASMC proliferation in vitro and PH in vivo, compared to that of normoxic PAEC. As we found that hypoxia exposure did not alter the number of PAECreleased MV, we reason that hypoxia exposure alters the cargo in PAEC-released MV and thereby their function to regulate PASMC proliferation and pathogenesis of PH. MicroRNAs (miRNAs, miRs) are small single-stranded non-coding RNAs and many of them have been identified to play important roles in disease development, including PH. Using miRNA deep sequencing analysis we found that, hypoxia exposure altered the miRNA cargo in PAEC-released MV: miR-210-3p level was increased, a miRNA that is known to stimulate SMC proliferation and induce PH. Meanwhile, hypoxia also induced a number of other miRNAs that inhibited SMC proliferation, principal among them being a novel miRNA, miR-212-5p, that had the highest inhibitory effect on SMC proliferation. Our data also showed that the endothelium and/or ECderived MV are critical for the induction of miR-212-5p in SMC in hypoxia as there was no induction of miRNA-212-5p in isolated SMC in hypoxia. Taking together, we hypothesize that EC-derived MV promote development of PH and vascular remodeling during hypoxia due to the presence of miRNA-210-3p but they may also provide a break against continued progression of the disease via anti-proliferative miRNAs, specifically miRNA-212-5p.