Abstract 5547: CXCR4 Signaling Exacerbates Vein Graft Neointimal Hyperplasia
Vein graft neointimal hyperplasia can cause vein graft failure directly or, by promoting accelerated atherosclerosis, indirectly. Because most vein graft neointimal cells originate from outside the vein graft, and because CXCR4, the SDF-1α receptor, contributes significantly to recruitment of vascular progenitor cells, we tested the hypothesis that CXCR4 activity exacerbates vein graft neointimal hyperplasia. We performed carotid artery interposition vein grafting in congenic WT and cxcr4−/+ mice, using the inferior vena cava of WT and cxcr4−/+ mice as vein grafts. We created 3 surgically chimeric groups, designated by vein graft donor/vein graft recipient: WT/WT, cxcr4−/+/WT, and cxcr4−/+/cxcr4−/+. Immunofluorescence for SDF-1, the CXCR4 agonist, was evident in 2-wk-old vein grafts (with expanding neointimas), but not in 6-wk-old vein grafts (in which neointimal hyperplasia had reached steady state). In 6-wk-old WT/WT, cxcr4−/+/WT, and cxcr4−/+/cxcr4−/+ vein grafts, respectively, neointimal areas were 0.12 ± 0.01, 0.118 ± 0.008, and 0.066 ± 0.008 mm2, while medial areas were 0.20 ± 0.02, 0.26 ± 0.01, and 0.32 ± 0.02 mm2. Thus, relative to WT/WT grafts, neointimal area was reduced only in cxcr4−/+/cxcr4−/+ vein grafts, by 47% (p<0.01), while medial area was increased in cxcr4−/+/WT and cxcr4−/+/cxcr4−/+ vein grafts, by 26% and 56%, respectively (p<0.05). However, vein graft re-endothelialization was equivalent in all 3 vein graft groups (judged by immunostaining for Tie2). SMC-like cells comprised 100% of neointimal cells, but < 50% of medial cells. In cxcr4−/+/cxcr4−/+ vein grafts, however, the prevalence of medial SMC actin-positive cells was 45±20% greater than in WT/WT grafts (p<0.04), while the prevalence of collagen I-positive cells was 40±5% less (p<0.01), as assessed by quantitative immunofluorescence. We conclude that CXCR4 contributes to vein graft neointimal hyperplasia through endothelium-independent mechanisms that alter homing of graft-extrinsic cells to the vein graft. Moreover, while CXCR4 activity augments neointimal hyperplasia, it reduces the medial hypertrophy that is believed to be desirable for reducing vein graft wall stress. These results suggest that CXCR4 antagonist therapy may alleviate vein graft disease.