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^δCT) 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^δCT mice showed a comparable regression of the superficial vascular plexus during the initial exposure of mice to hyperoxia. However, TF^δCT 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^δCT mice to revascularization rates observed in wild-type mice. Genetic deletion of PAR2, but not of PAR1, abolished enhanced revascularization of TF^δCT 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.