Published Online
on July 23, 2007

A more recent version of this article appeared on August 14, 2007

This Article Full Text (PDF) Data Supplement Data Supplement All Versions of this Article: 116/7/774    most recent CIRCULATIONAHA.107.701516v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Takeda, K. Articles by Fong, G.-H. Search for Related Content PubMed PubMed Citation Articles by Takeda, K. Articles by Fong, G.-H. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB OXYGEN TAMOXIFEN Related Collections Angiogenesis Other Vascular biology

Submitted on March 8, 2007
Accepted on May 21, 2007

Essential Role for Prolyl Hydroxylase Domain Protein 2 in Oxygen Homeostasis of the Adult Vascular System

Kotaro Takeda MD, PhD, Ann Cowan PhD, and Guo-Hua Fong PhD^*

From the Center for Vascular Biology, Center for Biomedical Imaging Technology, Department of Cell Biology, University of Connecticut Health Center, Farmington.

^* To whom correspondence should be addressed. E-mail: fong{at}nso2.uchc.edu.

Background--Prolyl hydroxylase domain (PHD) proteins, including PHD1, PHD2, and PHD3, mediate oxygen-dependent degradation of hypoxia-inducible factor (HIF)- subunits. Although angiogenic roles of hypoxia-inducible factors are well known, the roles of PHDs in the vascular system remain to be established.

Methods and Results--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-1 and angiectasia in the liver were not accompanied by corresponding increases in hepatic expression of Vegfa or angiopoietin-1. However, the serum vascular endothelial growth factor-A level was significantly increased in PHD2-deficient mice.

Conclusions--PHD2, but not PHD1 and PHD3, is a major negative regulator for vascular growth in adult mice. Increased angiogenesis in PHD2-deficient mice may be mediated by a novel systemic mechanism.

Key words: angiogenesis • hypoxia • cardiovascular system

This article has been cited by other articles:

				J. A. Garcia Aiming Straight for the Heart: Prolyl Hydroxylases Set the BAR Sci. Signal., November 10, 2009; 2(96): pe70 - pe70. [Abstract] [Full Text] [PDF]

				S. Barth, F. Edlich, U. Berchner-Pfannschmidt, S. Gneuss, G. Jahreis, P. A. Hasgall, J. Fandrey, R. H. Wenger, and G. Camenisch Hypoxia-inducible Factor Prolyl-4-hydroxylase PHD2 Protein Abundance Depends on Integral Membrane Anchoring of FKBP38 J. Biol. Chem., August 21, 2009; 284(34): 23046 - 23058. [Abstract] [Full Text] [PDF]

				K. C. Kanelakis, H. L. Palomino, L. Li, J. Wu, W. Yan, M. D. Rosen, M. C. Rizzolio, M. Trivedi, M. F. Morton, Y. Yang, et al. Characterization of a Robust Enzymatic Assay for Inhibitors of 2-Oxoglutarate-Dependent Hydroxylases J Biomol Screen, July 1, 2009; 14(6): 627 - 635. [Abstract] [PDF]

				K. Schultz, V. Murthy, J. B. Tatro, and D. Beasley Prolyl hydroxylase 2 deficiency limits proliferation of vascular smooth muscle cells by hypoxia-inducible factor-1{alpha}-dependent mechanisms Am J Physiol Lung Cell Mol Physiol, June 1, 2009; 296(6): L921 - L927. [Abstract] [Full Text] [PDF]

				T. Miyata and C. van Ypersele de Strihou Translation of basic science into clinical medicine: novel targets for diabetic nephropathy Nephrol. Dial. Transplant., May 1, 2009; 24(5): 1373 - 1377. [Full Text] [PDF]

				C. Ladroue, R. Carcenac, M. Leporrier, S. Gad, C. Le Hello, F. Galateau-Salle, J. Feunteun, J. Pouyssegur, S. Richard, and B. Gardie PHD2 Mutation and Congenital Erythrocytosis with Paraganglioma N. Engl. J. Med., December 18, 2008; 359(25): 2685 - 2692. [Abstract] [Full Text] [PDF]

				J.-X. Chen and A. Stinnett Ang-1 Gene Therapy Inhibits Hypoxia-Inducible Factor-1{alpha} (HIF-1{alpha})-Prolyl-4-Hydroxylase-2, Stabilizes HIF-1{alpha} Expression, and Normalizes Immature Vasculature in db/db Mice Diabetes, December 1, 2008; 57(12): 3335 - 3343. [Abstract] [Full Text] [PDF]

				K. Takeda, H. L. Aguila, N. S. Parikh, X. Li, K. Lamothe, L.-J. Duan, H. Takeda, F. S. Lee, and G.-H. Fong Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins Blood, March 15, 2008; 111(6): 3229 - 3235. [Abstract] [Full Text] [PDF]

				E. I. Chang, S. A. Loh, D. J. Ceradini, E. I. Chang, S.-e Lin, N. Bastidas, S. Aarabi, D. A. Chan, M. L. Freedman, A. J. Giaccia, et al. Age Decreases Endothelial Progenitor Cell Recruitment Through Decreases in Hypoxia-Inducible Factor 1{alpha} Stabilization During Ischemia Circulation, December 11, 2007; 116(24): 2818 - 2829. [Abstract] [Full Text] [PDF]