Loss of prolyl hydroxylase domain protein 2 in vascular endothelium increases pericyte coverage and promotes pulmonary arterial remodeling.
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.
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, MS, USA.
Shuo
S
Wang
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, MS, USA.
Heng
H
Zeng
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, MS, USA.|School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China.
Xue-Jiao
XJ
Xie
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, MS, USA.
Yong-Kang
YK
Tao
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, MS, USA.
Xiaochen
X
He
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, MS, USA.
Richard J
RJ
Roman
Department of Pediatrics, Albert Einstein College of Medicine and The Children's Hospital at Montefiore, Bronx, NY, USA.
Judy L
JL
Aschner
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, MS, USA.|School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China.
Jian-Xiong
JX
Chen
D000818:Animals; D006332:Cardiomegaly / Q000235:genetics; D004452:Echocardiography; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020286:Pericytes / Q000473:pathology*; D011651:Pulmonary Artery / Q000473:pathology*; D000071656:Receptor, Notch3 / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D017540:Tunica Media / Q000473:pathology*; D066253:Vascular Remodeling / Q000235:genetics
D000071656:Receptor, Notch3; D016212:Transforming Growth Factor beta; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
HIF; Pathology Section; endothelial; prolyl hydroxylase-2; pulmonary hypertension