Endothelial Autocrine Signaling through CXCL12/CXCR4/FoxM1 Axis Contributes to Severe Pulmonary Arterial Hypertension

Int J Mol Sci. 2021 Mar 20;22(6):3182. doi: 10.3390/ijms22063182.


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, Egln1Tie2Cre (Tie2Cre-mediated disruption of Egln1) mice, to identify the novel autocrine signaling mediating the pulmonary vascular endothelial cell (PVEC) proliferation and the pathogenesis of PAH. PVECs isolated from Egln1Tie2Cre 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 Cxcl12(Egln1/Cxcl12Tie2Cre) or AMD3100 treatment in Egln1Tie2Cre mice downregulated FoxM1 expression in vivo. We then generated and characterized a novel mouse model with endothelial specific FoxM1 deletion in Egln1Tie2Cre mice (Egln1/Foxm1Tie2Cre), 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.

Keywords: angiogenesis; endothelium; hypoxia; pulmonary hypertension; vascular remodeling.

MeSH terms

  • Animals
  • Autocrine Communication*
  • Biomarkers
  • Cells, Cultured
  • Chemokine CXCL12 / metabolism*
  • Disease Models, Animal
  • Endothelial Cells / metabolism*
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Fluorescent Antibody Technique
  • Forkhead Box Protein M1 / metabolism*
  • Humans
  • Hypoxia / metabolism
  • Immunohistochemistry
  • Mice
  • Mice, Transgenic
  • Pulmonary Arterial Hypertension / diagnosis
  • Pulmonary Arterial Hypertension / etiology*
  • Pulmonary Arterial Hypertension / metabolism*
  • Receptors, CXCR4 / metabolism*
  • Severity of Illness Index
  • Signal Transduction*
  • Vascular Remodeling


  • Biomarkers
  • CXCL12 protein, human
  • Chemokine CXCL12
  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • Receptors, CXCR4