This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 27/6/1456    most recent ATVBAHA.107.142539v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map 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 Uusitalo-Jarvinen, H. Articles by Ruf, W. Search for Related Content PubMed PubMed Citation Articles by Uusitalo-Jarvinen, H. Articles by Ruf, W. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB IMATINIB MESYLATE OXYGEN

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1456.)
© 2007 American Heart Association, Inc.

Thrombosis

Role of Protease Activated Receptor 1 and 2 Signaling in Hypoxia-Induced Angiogenesis

Hannele Uusitalo-Jarvinen; Toru Kurokawa; Barbara M. Mueller; Patricia Andrade-Gordon; Martin Friedlander; Wolfram Ruf

From the Department of Cell Biology (H.U.-J., M.F.) and Immunology (T.K., W.R.), The Scripps Research Institute, La Jolla, Calif; La Jolla Institute for Molecular Medicine (B.M.M.), San Diego, Calif; and Johnson & Johnson PRD (P.A.-G.), Spring House, Pa.

Correspondence to Wolfram Ruf, MD, PhD, or Martin Friedlander, MD, PhD, Department of Immunology, SP258, or Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail ruf{at}scripps.edu or friedlan@scripps.edu

Objective— Tissue factor (TF) initiates coagulation and indirectly triggers thrombin-dependent protease activated receptor (PAR) signaling. The TF–VIIa complex also directly cleaves PAR2 and promotes angiogenesis in vitro in TF cytoplasmic domain-deleted (TF^CT) mice. Here we address the effect of PAR1 and PAR2 deficiency on angiogenesis in vivo.

Methods and Results— In hypoxia-driven angiogenesis of oxygen induced retinopathy (OIR), wild-type, PAR1^–/–, PAR2^–/–, and TF^CT mice showed a comparable regression of the superficial vascular plexus during the initial exposure of mice to hyperoxia. However, TF^CT mice revascularized areas of central vaso-obliteration significantly faster than wild-type animals. Pharmacological inhibition of the TF–VIIa complex, but not of Xa, and blockade of tyrosine kinase receptor pathways with Gleevec reversed accelerated angiogenesis of TF^CT mice to revascularization rates observed in wild-type mice. Genetic deletion of PAR2, but not of PAR1, abolished enhanced revascularization of TF^CT mice. PAR1 knock-out animals were indistinguishable from wild-type mice in the model of retinal neoangiogenesis and angiogenesis-dependent subcutaneous tumor growth was unaltered in PAR1- and PAR2-deficient animals.

Conclusion— Loss of the TF cytoplasmic domain results in accelerated hypoxia-induced angiogenesis mediated by TF–VIIa signaling. PAR2 signaling is sufficient for this proangiogenic effect without apparent contributions of mouse host cell PAR1.

The TF pathway regulates angiogenesis through direct TF–VIIa signaling and potentially downstream coagulation activation and thrombin signaling. TF–VIIa-driven angiogenesis in TF cytoplasmic domain deleted mice is shown to be dependent on PAR2 signaling without significant contributions from downstream coagulation activation or mouse PAR1 signaling in vivo.

Key Words: tissue factor • protease activated receptors • angiogenesis • coagulation • thrombin

This article has been cited by other articles:

				F. Schaffner and W. Ruf Tissue Factor and PAR2 Signaling in the Tumor Microenvironment Arterioscler Thromb Vasc Biol, December 1, 2009; 29(12): 1999 - 2004. [Abstract] [Full Text] [PDF]

				H. H. Versteeg, F. Schaffner, M. Kerver, L. G. Ellies, P. Andrade-Gordon, B. M. Mueller, and W. Ruf Protease-Activated Receptor (PAR) 2, but not PAR1, Signaling Promotes the Development of Mammary Adenocarcinoma in Polyoma Middle T Mice Cancer Res., September 1, 2008; 68(17): 7219 - 7227. [Abstract] [Full Text] [PDF]

				A. Siegbahn, M. Johnell, A. Nordin, M. Aberg, and T. Velling TF/FVIIa Transactivate PDGFR to Regulate PDGF-BB Induced Chemotaxis in Different Cell Types: Involvement of Src And PLC Arterioscler Thromb Vasc Biol, January 1, 2008; 28(1): 135 - 141. [Abstract] [Full Text] [PDF]

				H. H. Versteeg, F. Schaffner, M. Kerver, H. H. Petersen, J. Ahamed, B. Felding-Habermann, Y. Takada, B. M. Mueller, and W. Ruf Inhibition of tissue factor signaling suppresses tumor growth Blood, January 1, 2008; 111(1): 190 - 199. [Abstract] [Full Text] [PDF]