Wu Kang, Tang Haiyang, Lin Ruizhu, Carr Shane G, Wang Ziyi, Babicheva Aleksandra, Ayon Ramon J, Jain Pritesh P, Xiong Mingmei, Rodriguez Marisela, Rahimi Shamin, Balistrieri Francesca, Rahimi Shayan, Valdez-Jasso Daniela, Simonson Tatum S, Desai Ankit A, Garcia Joe G N, Shyy John Y-J, Thistlethwaite Patricia A, Wang Jian, Makino Ayako, Yuan Jason X-J
Departments of Medicine and Physiology, The University of Arizona, Tucson, USA.
State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Pulm Circ. 2020 Sep 10;10(3):2045894020948470. doi: 10.1177/2045894020948470. eCollection 2020 Jul-Sep.
Platelet-derived growth factor is one of the major growth factors found in human and mammalian serum and tissues. Abnormal activation of platelet-derived growth factor signaling pathway through platelet-derived growth factor receptors may contribute to the development and progression of pulmonary vascular remodeling and obliterative vascular lesions in patients with pulmonary arterial hypertension. In this study, we examined the expression of platelet-derived growth factor receptor isoforms in pulmonary arterial smooth muscle and pulmonary arterial endothelial cells and investigated whether platelet-derived growth factor secreted from pulmonary arterial smooth muscle cell or pulmonary arterial endothelial cell promotes pulmonary arterial smooth muscle cell proliferation. Our results showed that the protein expression of platelet-derived growth factor receptor α and platelet-derived growth factor receptor β in pulmonary arterial smooth muscle cell was upregulated in patients with idiopathic pulmonary arterial hypertension compared to normal subjects. Platelet-derived growth factor activated platelet-derived growth factor receptor α and platelet-derived growth factor receptor β in pulmonary arterial smooth muscle cell, as determined by phosphorylation of platelet-derived growth factor receptor α and platelet-derived growth factor receptor β. The platelet-derived growth factor-mediated activation of platelet-derived growth factor receptor α/platelet-derived growth factor receptor β was enhanced in idiopathic pulmonary arterial hypertension-pulmonary arterial smooth muscle cell compared to normal cells. Expression level of platelet-derived growth factor-AA and platelet-derived growth factor-BB was greater in the conditioned media collected from idiopathic pulmonary arterial hypertension-pulmonary arterial endothelial cell than from normal pulmonary arterial endothelial cell. Furthermore, incubation of idiopathic pulmonary arterial hypertension-pulmonary arterial smooth muscle cell with conditioned culture media from normal pulmonary arterial endothelial cell induced more platelet-derived growth factor receptor α activation than in normal pulmonary arterial smooth muscle cell. Accordingly, the conditioned media from idiopathic pulmonary arterial hypertension-pulmonary arterial endothelial cell resulted in more pulmonary arterial smooth muscle cell proliferation than the media from normal pulmonary arterial endothelial cell. These data indicate that (a) the expression and activity of platelet-derived growth factor receptor are increased in idiopathic pulmonary arterial hypertension-pulmonary arterial smooth muscle cell compared to normal pulmonary arterial smooth muscle cell, and (b) pulmonary arterial endothelial cell from idiopathic pulmonary arterial hypertension patients secretes higher level of platelet-derived growth factor than pulmonary arterial endothelial cell from normal subjects. The enhanced secretion (and production) of platelet-derived growth factor from idiopathic pulmonary arterial hypertension-pulmonary arterial endothelial cell and upregulated platelet-derived growth factor receptor expression (and function) in idiopathic pulmonary arterial hypertension-pulmonary arterial smooth muscle cell may contribute to enhancing platelet-derived growth factor/platelet-derived growth factor receptor-associated pulmonary vascular remodeling in pulmonary arterial hypertension.
血小板衍生生长因子是在人类和哺乳动物血清及组织中发现的主要生长因子之一。通过血小板衍生生长因子受体使血小板衍生生长因子信号通路异常激活，可能会促进肺动脉高压患者肺血管重塑和闭塞性血管病变的发生与发展。在本研究中，我们检测了肺动脉平滑肌细胞和肺动脉内皮细胞中血小板衍生生长因子受体亚型的表达，并研究了肺动脉平滑肌细胞或肺动脉内皮细胞分泌的血小板衍生生长因子是否促进肺动脉平滑肌细胞增殖。我们的结果显示，与正常受试者相比，特发性肺动脉高压患者的肺动脉平滑肌细胞中血小板衍生生长因子受体α和血小板衍生生长因子受体β的蛋白表达上调。通过血小板衍生生长因子受体α和血小板衍生生长因子受体β的磷酸化测定发现，血小板衍生生长因子激活了肺动脉平滑肌细胞中的血小板衍生生长因子受体α和血小板衍生生长因子受体β。与正常细胞相比，特发性肺动脉高压-肺动脉平滑肌细胞中血小板衍生生长因子介导的血小板衍生生长因子受体α/血小板衍生生长因子受体β激活增强。特发性肺动脉高压-肺动脉内皮细胞收集的条件培养基中血小板衍生生长因子-AA和血小板衍生生长因子-BB的表达水平高于正常肺动脉内皮细胞。此外，用正常肺动脉内皮细胞的条件培养基孵育特发性肺动脉高压-肺动脉平滑肌细胞，比正常肺动脉平滑肌细胞诱导更多的血小板衍生生长因子受体α激活。因此，特发性肺动脉高压-肺动脉内皮细胞的条件培养基比正常肺动脉内皮细胞的培养基导致更多的肺动脉平滑肌细胞增殖。这些数据表明：（a）与正常肺动脉平滑肌细胞相比，特发性肺动脉高压-肺动脉平滑肌细胞中血小板衍生生长因子受体的表达和活性增加；（b）特发性肺动脉高压患者的肺动脉内皮细胞比正常受试者的肺动脉内皮细胞分泌更高水平的血小板衍生生长因子。特发性肺动脉高压-肺动脉内皮细胞中血小板衍生生长因子分泌（及产生）的增强以及特发性肺动脉高压-肺动脉平滑肌细胞中血小板衍生生长因子受体表达（及功能）的上调，可能有助于增强肺动脉高压中血小板衍生生长因子/血小板衍生生长因子受体相关的肺血管重塑。
