Remodeling of experimental arteriovenous fistula with increased matrix metalloproteinase expression in rats

Venous dilatation and wall thickening are part of the maturation of an arteriovenous fistula (AVF). However, the underlying mechanism of AVF remodeling remains unknown. We therefore studied whether matrix remodeling elicited by matrix metalloproteinases (MMPs) may contribute to AVF maturation.

A femoral AVF model in rats was established by invagination of the distal end of the left femoral artery into the femoral vein after venotomy (fistula group). In the sham group, the left femoral artery was cut, but venous invagination was not performed. Changes in the hemodynamics and the diameter of the iliac vein were studied on days 3, 14, and 28, then the iliac vein was removed and examined for changes in wall thickness and expression of MMP-2 and MMP-9, type 4 tissue inhibitor of metalloproteinases (TIMP-4), and collagen I and III by immunohistochemical staining or Western blotting.

Femoral AVF resulted in a sixfold increase in blood flow in the fistula iliac vein and a gradual, but significant, increase in the thickness of the intima and media and marked up-regulation of MMP-2 and MMP-9, down-regulation of TIMP-4, as well as degradation of collagens I and III. The collagen I/III ratio was significantly higher in the 14-day fistula group (1.44 +/- 0.32) than in the sham group (0.82 +/- 0.15) and was even higher in the 28-day fistula group (1.76 +/- 0.21).

The present results confirmed our hypothesis that a high blood flow rate in the fistula vein affects the expression of MMPs and TIMP-4, resulting in the remodeling or maturation of the AVF. Remodeling is associated with degradation of collagen, with an increase in the collagen I/III ratio.