Research Papers: Pathology:
Loss of prolyl hydroxylase domain protein 2 in vascular endothelium increases pericyte coverage and promotes pulmonary arterial remodeling
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Shuo Wang1,*, Heng Zeng1,*, Xue-Jiao Xie1,2, Yong-Kang Tao1, Xiaochen He1, Richard J. Roman1, Judy L. Aschner3 and Jian-Xiong Chen1,2
1 Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, MS, USA
2 School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
3 Department of Pediatrics, Albert Einstein College of Medicine and The Children’s Hospital at Montefiore, Bronx, NY, USA
* These authors have contributed equally to this work
Jian-Xiong Chen, email:
Keywords: endothelial, prolyl hydroxylase-2, HIF, pulmonary hypertension, Pathology Section
Received: July 20, 2016 Accepted: August 21, 2016 Published: August 24, 2016
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-α 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.
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