Role of protease activated receptor 1 and 2 signaling in hypoxia-induced angiogenesis.
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(deltaCT)) mice. Here we address the effect of PAR1 and PAR2 deficiency on angiogenesis in vivo.


RESULTS
In hypoxia-driven angiogenesis of oxygen induced retinopathy (OIR), wild-type, PAR1-/-, PAR2-/-, and TF(deltaCT) mice showed a comparable regression of the superficial vascular plexus during the initial exposure of mice to hyperoxia. However, TF(deltaCT) 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(deltaCT) mice to revascularization rates observed in wild-type mice. Genetic deletion of PAR2, but not of PAR1, abolished enhanced revascularization of TF(deltaCT) 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.


CONCLUSIONS
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.
Uusitalo-Jarvinen
Hannele
H
Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Kurokawa
Toru
T
Mueller
Barbara M
BM
Andrade-Gordon
Patricia
P
Friedlander
Martin
M
Ruf
Wolfram
W
D000818:Animals; D001549:Benzamides; D019774:Blood Coagulation Factor Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015942:Factor VIIa / Q000378:metabolism; D018496:Hyperoxia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D000860:Hypoxia / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D000068877:Imatinib Mesylate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D010100:Oxygen; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D044463:Receptor, PAR-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D044464:Receptor, PAR-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015861:Retinal Neovascularization / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D012171:Retinal Vessels / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D001549:Benzamides; D019774:Blood Coagulation Factor Inhibitors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D000068877:Imatinib Mesylate; D013925:Thromboplastin; D015942:Factor VIIa; D010100:Oxygen