Jul 25, 2007

Essential role for prolyl hydroxylase domain protein 2 in oxygen homeostasis of the adult vascular system

Circulation
Kotaro TakedaGuo-Hua Fong

Abstract

Prolyl hydroxylase domain (PHD) proteins, including PHD1, PHD2, and PHD3, mediate oxygen-dependent degradation of hypoxia-inducible factor (HIF)-alpha subunits. Although angiogenic roles of hypoxia-inducible factors are well known, the roles of PHDs in the vascular system remain to be established. We evaluated angiogenic phenotypes in mice carrying targeted disruptions in genes encoding different PHD isoforms. Although Phd1-/- and Phd3-/- mice did not display apparent angiogenic defects, broad-spectrum conditional knockout of Phd2 led to hyperactive angiogenesis and angiectasia. Blood vessels in PHD2-deficient mice were highly perfusable. Furthermore, examination of medium-sized vessels in subendocardial layer in the heart demonstrated successful recruitment of vascular smooth muscle cells. Surprisingly, increased vascular growth was independent of local efficiency of Phd2 disruption. Mice carrying significant Phd2 disruption in multiple organs, including the liver, heart, kidney, and lung, displayed excessive vascular growth not only in these organs but also in the brain, where Phd2 disruption was very inefficient. More surprisingly, increased accumulation of hypoxia-inducible factor-1alpha and angiectasia in the liver were no...Continue Reading

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  • Citations139

Citations

Mentioned in this Paper

Dioxygen
Immediate-Early Proteins
Lung
Angiogenic Process
Blood Vessel
Brain
VEGFA gene
Zitazonium
Egln1 protein, mouse
Hepatic

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