Vein graft neointimal hyperplasia is exacerbated by CXCR4 signaling in vein graft-extrinsic cells

Zhang L, Brian L, Freedman NJ (Duke Univ Med Ctr, Durham, NC) J Vasc Surg 56:1390-1397, 2012^§

Abstract

Objective

Because vein graft neointimal hyperplasia engenders vein graft failure, and because most vein graft neointimal cells derive from outside the vein graft, we sought to determine whether vein graft neointimal hyperplasia is affected by activity of the CXC chemokine receptor-4 (CXCR4), which is important for bone marrow-derived cell migration.

Methods

In congenic Cxcr4^−/+ and wild-type (WT) recipient mice, we performed interposition grafting of the common carotid artery with the inferior vena cava (IVC) of either Cxcr4^−/+ or WT mice to create four surgically chimeric groups of mice (n ≥ 5 each), characterized by vein graft donor/recipient: WT/WT; Cxcr4^−/+/WT; WT/Cxcr4^−/+; and Cxcr4^−/+/Cxcr4^−/+; vein grafts were harvested 6 weeks postoperatively.

Results

The agonist for CXCR4 is expressed by cells in the arterializing vein graft. Vein graft neointimal hyperplasia was reduced by reducing CXCR4 activity in vein graft-extrinsic cells, but not in vein graft-intrinsic cells: the rank order of neointimal hyperplasia was WT/WT ≈ Cxcr4^−/+/WT > WT/Cxcr4^−/+ ≈ Cxcr4^−/+/Cxcr4^−/+; CXCR4 deficiency in graft-extrinsic cells reduced neointimal hyperplasia by 39% to 47% (P < .05). Vein graft medial area was equivalent in all grafts except Cxcr4^−/+/Cxcr4^−/+, in which the medial area was 60% ± 20% greater (P < .05). Vein graft re-endothelialization was indistinguishable among all three vein graft groups. However, the prevalence of medial leukocytes was 40% ± 10% lower in Cxcr4^−/+/Cxcr4^−/+ than in WT/WT vein grafts (P < .05), and the prevalence of smooth muscle actin-positive cells was 45% ± 20% higher (P < .05).

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