Abstract 470: Murine Tissue Factor Pathway Inhibitor-2 Aggravates Injury-Induced Hyperplasia But Reduces Plaque Stability
Background: Tissue factor pathway inhibitor-2 (TFPI-2), a serine protease inhibitor, was recently shown to target not only tissue factor but also plasmin and MMPs. Moreover, it was found to be highly expressed by advanced human atherosclerotic lesions. Though plausible, a contribution of TFPI-2 to vascular pathobiologies has not yet been established. In this study we set out to address the involvement of TFPI-2 in vasculopathies such as atherosclerosis and restenosis by a gain-of-function approach.
Results: Murine TFPI-2 adenovirus was generated and shown functional in that adenovirus derived mTFPI-2 was able to increase tissue factor-dependent plasma coagulation time by 12-fold (P=0.002). To investigate its role in intimal hyperplasia after carotid guide wire injury in ApoE−/ − mice, Ad.mTFPI-2 was, at the time of vascular injury, locally delivered to the carotid artery (n=22). Compared to Ad.empty treated control mice, Ad.mTFPI-2 treatment was seen to impair re-endothelialization of the injured vessel (−72%; P=0.002), leading to an accelerated influx of leukocytes and to an increase in neointima formation (+55%; P=0.03). Mouse TFPI-2 acted anti-mitogenic on endothelial cells (−97%; P<0.005) and blocked their migration and sprouting on growth factor-reduced Matrigel (−83%; P<0.005). Similarly, Ad.mTFPI-2 infection led to a clear inhibition of smooth muscle cell migration and proliferation (P=0.0003). To evaluate the role of mTFPI-2 in atherosclerosis, a carotid artery segment was instilled transluminally with Ad.mTFPI-2 (or Ad.Empty control) in an established model of flow-induced collar-aided atherogenesis. Mouse TFPI-2 overexpression did not affect plaque, media or vessel size. However, the plaque collagen content was significantly decreased compared with Ad.Empty controls (−62%; P=0.01), which was accompanied by an increase in necrotic core area (+67%; P=0.05), pointing to a more vulnerable plaque phenotype.
Conclusions: the serine protease inhibitor mTFPI-2 contributes to various inflammatory vasculopathies such as restenosis and atherosclerosis, in part by virtue of its anti-angiogenic activity.