Initial Inhibition of Tissue Factor Signalling Reduces Chronic Vascular Changes in Isogenic Rat Aortic Transplants

Abstract

Vascular changes are considered the major histopathological indicator of chronic allograft dysfunction. These changes are characterized by intimal thickening caused by accumulation of primarily smooth muscle cells. Contributing factors may be of both immunological and nonimmunological origin. Cold ischemia has been shown to trigger intimal proliferation in the absence of alloantigen in an isogenic rat aortic transplant model. We have used this model to investigate the impact of inhibition of tissue factor (TF) signalling on the progression of intimal thickening. Group 1 was treated with recombinant FVIIa inhibited in its active site (rFVIIai), and group 2 served as untreated controls. At 8 weeks the intimal area was measured with image analysis. Medial areas and the proportion of medial necrosis were determined. Animals treated with rFVIIai showed significantly less intimal thickening compared with controls: median 0.147 vs. 0.256 mm2, respectively (p=0.008). A positive correlation between intimal hyperplasia and medial necrosis (rs = 0.79, p = 0.01), as well as adventitial inflammation (rs = 0.83, p = 0.009), was found. TF mRNA was not detected in the neointima at 8 weeks, as determined by in situ hybridization. We conclude that active site inhibited FVIIa (rFVIIai) given prior to and directly after implantation of aortic transplants significantly reduces intimal hyperplasia caused by nonimmunological factors in this model.