Loss of prolyl hydroxylase domain protein 2 in vascular endothelium increases pericyte coverage and promotes pulmonary arterial remodeling

Shuo Wang, Heng Zeng, Xue Jiao Xie, Yong Kang Tao, Xiaochen He, Richard J. Roman, Judy L. Aschner, Jian Xiong Chen

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Pulmonary arterial hypertension (PAH) is a leading cause of heart failure. Although pulmonary endothelial dysfunction plays a crucial role in the progression of the PAH, the underlying mechanisms are poorly understood. The HIF-a hydroxylase system is a key player in the regulation of vascular remodeling. Knockout of HIF-2α has been reported to cause pulmonary hypertension. The present study examined the role of endothelial cell specific prolyl hydroxylase-2 (PHD2) in the development of PAH and pulmonary vascular remodeling. The PHD2f/f mouse was crossbred with VE-Cadherin-Cre promoter mouse to generate an endothelial specific PHD2 knockout (Cdh5-Cre-PHD2ECKO) mouse. Pulmonary arterial pressure and the size of the right ventricle was significantly elevated in the PHD2ECKO mice relative to the PHD2f/f controls. Knockout of PHD2 in EC was associated with vascular remodeling, as evidenced by an increase in pulmonary arterial media to lumen ratio and number of muscularized arterioles. The pericyte coverage and vascular smooth muscle cells were also significantly increased in the PA. The increase in vascular pericytes was associated with elevated expression of fibroblast specific protein-1 (FSP-1). Moreover, perivascular interstitial fibrosis of pulmonary arteries was significantly increased in the PHD2ECKO mice. Mechanistically, knockout of PHD2 in EC increased the expression of Notch3 and transforming growth factor (TGF-β) in the lung tissue. We conclude that the expression of PHD2 in endothelial cells plays a critical role in preventing pulmonary arterial remodeling in mice. Increased Notch3/TGF-β signaling and excessive pericyte coverage may be contributing to the development of PAH following deletion of endothelial PHD2.

Original languageEnglish (US)
Pages (from-to)58848-58861
Number of pages14
JournalOncotarget
Volume7
Issue number37
DOIs
StatePublished - 2016

Keywords

  • Endothelial
  • HIF
  • Pathology Section
  • Prolyly hydroxylase-2
  • Pulmonary hypertension

ASJC Scopus subject areas

  • Oncology

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    Wang, S., Zeng, H., Xie, X. J., Tao, Y. K., He, X., Roman, R. J., Aschner, J. L., & Chen, J. X. (2016). Loss of prolyl hydroxylase domain protein 2 in vascular endothelium increases pericyte coverage and promotes pulmonary arterial remodeling. Oncotarget, 7(37), 58848-58861. https://doi.org/10.18632/oncotarget.11585