thromboplastin and Retinal-Neovascularization

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.. 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.. 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.

Topics: Animals; Benzamides; Blood Coagulation Factor Inhibitors; Cell Line, Tumor; Disease Models, Animal; Factor VIIa; Hyperoxia; Hypoxia; Imatinib Mesylate; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neoplasms, Experimental; Neovascularization, Pathologic; Oxygen; Piperazines; Protein Kinase Inhibitors; Pyrimidines; Receptor, PAR-1; Receptor, PAR-2; Retinal Neovascularization; Retinal Vessels; Signal Transduction; Thromboplastin; Time Factors