肺血管细胞异常相互作用是肺动脉高压（PH）血管重构的重要因素。近期发现除旁分泌外，外泌体在内皮-平滑肌细胞相互作用中扮演重要角色。已知富含H19的外泌体介导了多种疾病时细胞间相互作用。申请人前期发现lncRNA-H19与PH血管重构相关，但外泌体H19在PH中的作用还无报道。预实验发现低氧大鼠血浆外泌体高表达H19，且主要来源内皮；低氧肺动脉内皮细胞（PAEC）外泌体富含H19且可促进肺动脉平滑肌细胞（PASMC）增殖/迁移；PASMC干扰H19可显著抑制该作用。因此，我们推测外泌体H19介导了PH时PAEC与PASMC相互作用。本项目拟通过在体动物与细胞实验相结合，阐明外泌体H19促PH血管重构作用，并探讨潜在的上游（H19/Sirt1/V-ATPase通路）及下游机制（let-7g/c-Myc/Bmi-1/p16通路）。本项目将有助于阐明PH的发病机制，为寻找防治PH的新靶点奠定基础。

In the pulmonary vasculature, the endothelial and smooth muscle cells are two key cell types that play a major role in the pathobiology of pulmonary vascular disease and pulmonary hypertension. The normal interactions between these two cell types are important for the homeostasis of the pulmonary circulation, and any aberrant interaction between them may lead to various disease states including pulmonary vascular remodeling and pulmonary hypertension. It is well recognized that the endothelial cell can regulate the function of the underlying smooth muscle cell by releasing various bioactive agents such as nitric oxide and endothelin-1. In addition to such paracrine regulation, emerging evidence suggests that nonparacrine mechanism such as information transfer via exosomes plays an important role in the regulation of pulmonary vascular tone and the determination of cell phenotype and that they are critically involved in the pathobiology of pulmonary hypertension. H19-rich exosomes are known to mediate cellular interactions in a variety of diseases. Our group found lncRNA-H19 associated with vascular remodeling in PH. However, the role of exosomal H19 in PH remains unknown. Our pilot study showed that H19 is highly expressed in the plasma exosomes of hypoxic rats which is mainly derived from endothelium. Hypoxic pulmonary artery endothelial cells (PAECs) exosomes are rich in H19 and can promote the proliferation / migration of pulmonary artery smooth muscle cells (PASMCs). This effect is significantly suppressed after transfected H19 siRNA in PASMCs. Therefore, we hypothesized that exosomal H19 mediates the interaction between PAEC and PASMC during pulmonary vascular remodeling in PH. We will be planning to explore the important potential role of exosomal H19 in the pulmonary vascular remodeling in PH rats and cocultured PAECs and PASMCs. Furthermore, we will investigate the underlying mechanisms responsible for the up-regulation of exosomal H19 secreted from PAECs in hypoxia-induced PH rats (focusing on H19/Sirt1/V-ATPase signaling pathway) and the downstream signaling that exosomal H19 secreted from PAECs in promoting PASMCs proliferation/migration (focusing on let-7g/c-Myc/Bmi-1/p16 signaling pathway). This study will contribute to the understanding of pathogenesis of PH, and provide new strategies to seek for the new drugs directing at exosomal H19 target.