Characterization of neointima lesions associated with arteriovenous fistulas in a mouse model

Arteriovenous fistulas (AVFs) are usually used for vascular access in the provision of hemodialysis, but AVFs have a 1-year patency rate of only about 60% owing to stenosis. As the molecular mechanisms behind AVF neointimal hyperplasia remain largely unknown, representative models in transgenic mice could be useful to study this process at the genetic level. Hence, we characterized neointimal lesion formation in a model of AVF recently developed in the mouse, where the common carotid artery was end-to-side sutured to jugular vein in C57BL/6J mice. At the site of anastomosis, arterial wall thickening was observed as early as 1 week after surgery (fourfold) and progressed to six- and 10-fold original thickness in carotid arteries after 2 and 3 weeks, respectively. The lumen of the carotid artery was significantly narrowed owing to neointima 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 abundant smooth muscle cells (alpha-actin(+)) and a small number of membrane attack complex-1+ macrophages. Furthermore, using chimeric mice receiving bone marrow from transgenic mice expressing the LacZ gene in smooth muscle (SM-LacZ), it was found that bone marrow stem cells did not contribute to smooth muscle cell accumulation in neointimal lesions of AVF arteries. Thus, this model, which reproduces many of the features of human AVF, 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.