Abstract
Endothelial dysfunction is a pivotal initiating factor in vascular remodeling in pulmonary hypertension. EGLN3, a hypoxia response factor, plays a significant role in cell proliferation and angiogenesis, which are closely related to the pathophysiological conditions of pulmonary hypertension. This study investigates the potential involvement of EGLN3 in the injury response of pulmonary vascular endothelial cells and its contribution to the development of pulmonary arterial hypertension. Research has demonstrated that in patients with pulmonary arterial hypertension and various animal models of the condition, EGLN3 expression is upregulated in the remodeled pulmonary artery endothelium. Notably, the endothelial cell-specific knockout of EGLN3 can decelerate the progression of pulmonary arterial hypertension, whereas its overexpression has the opposite effect. Mechanistic analyses reveal that under hypoxic conditions, JUN initiates the transcription of EGLN3 by binding to its promoter region. Subsequently, EGLN3 interacts with HUR to enhance the stability of EGFR mRNA, thereby activating the PI3K/AKT and MAPK signaling pathways, which ultimately results in endothelial cell damage, proliferation, and migration. These findings suggest that EGLN3 is a critical gene for maintaining endothelial function and vascular homeostasis and holds promise as a novel therapeutic target for the treatment of pulmonary hypertension.