Differential gene expression patterns in vein regions susceptible versus resistant to neointimal hyperplasia.

Abstract

Arteriovenous hemodialysis graft (AVG) stenosis results in thrombosis and AVG failure, but prevention of stenosis has been unsuccessful due in large part to our limited understanding of the molecular processes involved in neointimal hyperplasia (NH) formation. AVG stenosis develops chiefly as a consequence of highly localized NH formation in the vein-graft anastomosis region. Surprisingly, the vein region just downstream of the vein-graft anastomosis (herein termed proximal vein region) is relatively resistant to NH. We hypothesized that the gene expression profiles of the NH-prone and NH-resistant regions will be different from each other after graft placement, and analysis of their genomic profiles may yield potential therapeutic targets to prevent AVG stenosis. To test this, we evaluated the vein-graft anastomosis (NH-prone) and proximal vein (NH-resistant) regions in a porcine model of AVG stenosis with a porcine microarray. Gene expression changes in these two distinct vein regions, relative to the gene expression in unoperated control veins, were examined at early (5 days) and later (14 days) time points following graft placement. Global genomic changes were much greater in the NH-prone region than in the NH-resistant region at both time points. In the NH-prone region, genes related to regulation of cell proliferation and osteo-/chondrogenic vascular remodeling were most enriched among the significantly upregulated genes, and genes related to smooth muscle phenotype were significantly downregulated. These results provide insights into the spatial and temporal genomic modulation underlying NH formation in AVG and suggest potential therapeutic strategies to prevent and/or limit AVG stenosis.