Growth Differentiation Factor 11 Promotes Abnormal Proliferation and Angiogenesis of Pulmonary Artery Endothelial Cells

Abstract

Disordered proliferation and angiogenesis of pulmonary artery endothelial cells is an important stage in the development of pulmonary arterial hypertension. Recent studies revealed that GDF11 (growth differentiation factor 11) induces endothelial cells proliferation and migration; however, whether GDF11 is directly involved in the pathogenesis of pulmonary arterial hypertension remains unknown. Here, we found that GDF11 was significantly upregulated and activated in 2 experimental pulmonary arterial hypertension models and cultured pulmonary artery endothelial cells. Genetic ablation of gdf11 in endothelial cells rescued pulmonary arterial hypertension features, as demonstrated by right ventricle hypertrophy, right ventricular systolic pressure, hemodynamics, cardiac function, and vascular remodeling. Moreover, we found that hypoxia significantly increased cell cycle progression, proliferation, migration, adhesion, and tube formation, which were significantly inhibited by GDF11 small interfering RNA. These events could be reproduced using cultured pulmonary artery endothelial cells and were dependent on Smad signaling. Moreover, hypoxia-induced GDF11 expression was regulated by the transcription factor zinc finger protein 740, which assisted RNA polymerase in recognizing and binding to the GDF11 promoter sequence located at a site (−753/−744; CCCCCCCCAC) upstream of the gene. This study identified a novel growth and differentiation factor signaling pathway involved in the zinc finger protein 740/GDF11/transforming growth factor-β receptor I/Smad signaling axis and involved in pulmonary artery endothelial cells proliferation and angiogenesis. These results provide critical insights for the development of novel therapeutic strategies for pulmonary arterial hypertension involving components of the GDF11 signaling system.