Find in Library

Endothelial autocrine signaling is essential to maintain vascular homeostasis. There is limited information about the role of endothelial autocrine signaling in regulating severe pulmonary vascular remodeling during the onset of pulmonary arterial hypertension (PAH). In this study, we employed the first severe pulmonary hypertension (PH) mouse model, <i>Egln1^Tie2Cre</i> (<i>Tie2Cre</i>-mediated disruption of <i>Egln1</i>) mice, to identify the novel autocrine signaling mediating the pulmonary vascular endothelial cell (PVEC) proliferation and the pathogenesis of PAH. PVECs isolated from <i>Egln1^Tie2Cre</i> lung expressed upregulation of many growth factors or angiocrine factors such as CXCL12, and exhibited pro-proliferative phenotype coincident with the upregulation of proliferation-specific transcriptional factor FoxM1. Treatment of CXCL12 on PVECs increased FoxM1 expression, which was blocked by CXCL12 receptor CXCR4 antagonist AMD3100 in cultured human PVECs. The endothelial specific deletion of <i>Cxcl12</i><i>(Egln1/Cxcl12^Tie2Cre</i>) or AMD3100 treatment <i>in Egln1^Tie2Cre</i> mice downregulated FoxM1 expression in vivo. We then generated and characterized a novel mouse model with endothelial specific FoxM1 deletion in <i>Egln1^Tie2Cre</i> mice (<i>Egln1/Foxm1^Tie2Cre</i>), and found that endothelial FoxM1 deletion reduced pulmonary vascular remodeling and right ventricular systolic pressure. Together, our study identified a novel mechanism of endothelial autocrine signaling in regulating PVEC proliferation and pulmonary vascular remodeling in PAH.