Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center.
Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen, Guangdong, China.
J Hypertens. 2022 Sep 1;40(9):1795-1807. doi: 10.1097/HJH.0000000000003220. Epub 2022 Jul 25.
Pulmonary hypertension is a lethal disease characterized by pulmonary vascular remodeling and is mediated by abnormal proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Platelet-derived growth factor BB (PDGF-BB) is the most potent mitogen for PASMCs and is involved in vascular remodeling in pulmonary hypertension development. Therefore, the objective of our study is to identify novel mechanisms underlying vascular remodeling in pulmonary hypertension.
We explored the effects and mechanisms of PTPRD downregulation in PASMCs and PTPRD knockdown rats in pulmonary hypertension induced by hypoxia.
We demonstrated that PTPRD is dramatically downregulated in PDGF-BB-treated PASMCs, pulmonary arteries from pulmonary hypertension rats, and blood and pulmonary arteries from lung specimens of patients with hypoxic pulmonary arterial hypertension (HPAH) and idiopathic PAH (iPAH). Subsequently, we found that PTPRD was downregulated by promoter methylation via DNMT1. Moreover, we found that PTPRD knockdown altered cell morphology and migration in PASMCs via modulating focal adhesion and cell cytoskeleton. We have demonstrated that the increase in cell migration is mediated by the PDGFRB/PLCγ1 pathway. Furthermore, under hypoxic condition, we observed significant pulmonary arterial remodeling and exacerbation of pulmonary hypertension in heterozygous PTPRD knock-out rats compared with the wild-type group. We also demonstrated that HET group treated with chronic hypoxia have higher expression and activity of PLCγ1 in the pulmonary arteries compared with wild-type group.
We propose that PTPRD likely plays an important role in the process of pulmonary vascular remodeling and development of pulmonary hypertension in vivo .
肺动脉高压是一种致命性疾病，其特征为肺血管重构，由肺动脉平滑肌细胞（PASMCs）的异常增殖和迁移介导。血小板衍生生长因子 BB（PDGF-BB）是 PASMCs 最有效的有丝分裂原，参与肺动脉高压发展中的血管重构。因此，本研究旨在确定肺动脉高压中血管重构的新机制。
我们研究了 PDGF-BB 处理的 PASMCs 中 PTPRD 下调以及缺氧诱导的肺动脉高压大鼠中 PTPRD 敲低的作用和机制。
我们证明 PDGF-BB 处理的 PASMCs、肺动脉高压大鼠的肺血管以及缺氧性肺动脉高压（HPAH）和特发性肺动脉高压（iPAH）患者的血液和肺血管中 PTPRD 明显下调。随后，我们发现 PTPRD 通过 DNMT1 介导的启动子甲基化而下调。此外，我们发现 PTPRD 敲低通过调节焦点黏附和细胞细胞骨架改变 PASMCs 的细胞形态和迁移。我们已经证明，细胞迁移的增加是由 PDGFRB/PLCγ1 途径介导的。此外，在缺氧条件下，与野生型组相比，杂合型 PTPRD 敲除大鼠观察到明显的肺动脉重构和肺动脉高压加重。我们还证明，与野生型组相比，慢性缺氧处理的 HET 组的肺血管中 PLCγ1 的表达和活性更高。
我们提出 PTPRD 可能在体内肺血管重构和肺动脉高压的发展过程中发挥重要作用。
