Inhibition of miR-495 Improves Both Vascular Remodeling and Angiogenesis in Pulmonary Hypertension

Background and Aims: Pulmonary hypertension (PH) is a chronic progressing vascular disease characterized by pulmonary arteriole remodeling and loss of pulmonary microvasculature. The aim of this study was to investigate a potential role for the miR-495 in PH pathogenesis and to explore its therapeutic potential in PH. Methods: Male C57BL/6J mice were injected with SU5416 weekly during 3 weeks of exposure to 10% oxygen to cause PH. We first tested the effects of adeno-associated virus 9 (AAV9) delivery which was specifically designed to block miR-495 in the lungs of the PH model. Then, the biological function of miR-495 was analyzed in cultured pulmonary arterial endothelial cells (PAECs) under hypoxic condition. Results: The inhibition of miR-495 improves hemodynamics and vascular remodeling in PH. At the same time, these effects were associated with increases in angiogenic transcription factor VEZF1 and marked upregulation of other angiogenic genes such as Angpt-1 and IGF1. In vitro, cultured mouse PAECs were transfected with miR-495 inhibitor or miR-495 mimics. Both the flow cytometry results and CCK8 assay showed that miR-495 inhibitor increased the percentage of cells in the G2/M+S phase, and the wound healing assays indicated that the migration capacity of PAECs transfected with miR-495 inhibitor was increased compared to the inhibitor-NC cells. Conclusions: Our results indicate that AAV9-TuD-miR-495 delivery improves hemodynamic and pulmonary vascular structural changes in PH mice.