on March 15, 2007
Published online before print March 15, 2007, doi: 10.1161/ATVBAHA.107.142539
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Submitted on January 14, 2007
Accepted on February 21, 2007
Role of Protease Activated Receptor 1 and 2 Signaling in Hypoxia-Induced Angiogenesis
Hannele Uusitalo-Jarvinen ;
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.
* To whom correspondence should be addressed. E-mail: ruf{at}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 TFCT mice showed a comparable regression of the superficial vascular plexus during the initial exposure of mice to hyperoxia. However, TFCT 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 TFCT mice to revascularization rates observed in wild-type mice. Genetic deletion of PAR2, but not of PAR1, abolished enhanced revascularization of TFCT 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.
Key words: tissue factor • protease activated receptors • angiogenesis • coagulation • thrombin
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