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

by 1, 1, 1, 2, 3,4, 3,4,5,6 and 1,*
1
Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ 85004, USA
2
Department of Preventative Medicine, Zhejiang Provincial Key Laboratory of Pathophysiology Technology, Medical School of Ningbo University, Ningbo 315211, China
3
Program for Lung and Vascular Biology, Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA
4
Department of Pediatrics, Division of Critical Care, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
5
Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
6
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
*
Author to whom correspondence should be addressed.
Academic Editors: Andrea Olschewski, Valentina Biasin, Chandran Nagaraj and Bence Nagy
Int. J. Mol. Sci. 2021, 22(6), 3182; https://doi.org/10.3390/ijms22063182
Received: 11 February 2021 / Revised: 15 March 2021 / Accepted: 18 March 2021 / Published: 20 March 2021
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. View Full-Text
Keywords: hypoxia; vascular remodeling; angiogenesis; pulmonary hypertension; endothelium hypoxia; vascular remodeling; angiogenesis; pulmonary hypertension; endothelium
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MDPI and ACS Style

Yi, D.; Liu, B.; Wang, T.; Liao, Q.; Zhu, M.M.; Zhao, Y.-Y.; Dai, Z. Endothelial Autocrine Signaling through CXCL12/CXCR4/FoxM1 Axis Contributes to Severe Pulmonary Arterial Hypertension. Int. J. Mol. Sci. 2021, 22, 3182. https://doi.org/10.3390/ijms22063182

AMA Style

Yi D, Liu B, Wang T, Liao Q, Zhu MM, Zhao Y-Y, Dai Z. Endothelial Autocrine Signaling through CXCL12/CXCR4/FoxM1 Axis Contributes to Severe Pulmonary Arterial Hypertension. International Journal of Molecular Sciences. 2021; 22(6):3182. https://doi.org/10.3390/ijms22063182

Chicago/Turabian Style

Yi, Dan, Bin Liu, Ting Wang, Qi Liao, Maggie M. Zhu, You-Yang Zhao, and Zhiyu Dai. 2021. "Endothelial Autocrine Signaling through CXCL12/CXCR4/FoxM1 Axis Contributes to Severe Pulmonary Arterial Hypertension" International Journal of Molecular Sciences 22, no. 6: 3182. https://doi.org/10.3390/ijms22063182

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