P89	Characterization of neointimal lesions associated with arteriovenous fistulae in mouse model: contribution of progenitor cells.
1Y.Castier, 1S.Lehoux, 2Y.Hu, 2G.Fonteinos, 1A.Tedgui, 2X.Qingbo
1INSERM Centre de Recherche Cardiovasculaire Lariboisiere, Paris, FR; 2St George's University of London, London, GB.

Background: Arteriovenous fistulae (AVFs) are usually used for vascular access in the provision of hemodialysis, but AVFs have a 1-year patency rate of only about 60% due to stenosis. Since the molecular mechanisms causing AVF neointimal hyperplasia remain largely unknown, representative models in transgenic mice could be useful to study this process at the genetic level. Methods and Results: Hence we characterized neointimal lesion formation in a model of AVF developed in the mouse, where the common carotid artery was end-to-side sutured to the jugular vein in C57BL/6J mice. At the site of anastomosis, arterial wall thickening was observed as early as 1 week after surgery (4-fold) and progressed to 6- and 10-fold original thickness in carotid arteries after 2 and 3 weeks, respectively. The lumen of the carotid artery was significantly narrowed due to neointimal hyperplasia, and thrombosis was observed in the vein wall opposite to the anastomosed artery. Histological and immunohistochemical analyses revealed that 3-week neointimal lesions consisted of a significant proportion of vascular smooth muscle cells (alpha-actin+), and contained a small number of MAC-1+ macrophages. Furthermore, using chimeric mice receiving bone marrow from transgenic mice expressing the LacZ gene in either smooth muscle (SM-LacZ) or endothelial (TIE2-LacZ) cells, it was found that bone marrow stem cells contributed to regenerate endothelial cells (<10%) on the surface of neointimal lesions and to newly formed microvessels found within the lesion of fistulated arteries. Conclusions: We described the first mouse model of AVF, which reproduces many of the features of human AVF, and demonstrated the role of bone marrow progenitor cells in the development of neointimal lesions. This model should prove useful for our understanding of the mechanism of neointimal formation and to evaluate the effects of drugs and gene therapy on this disease.

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