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

Publication ,  Journal Article
Zhang, L; Brian, L; Freedman, NJ
Published in: J Vasc Surg
November 2012

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). CONCLUSIONS: We conclude that CXCR4 contributes to vein graft neointimal hyperplasia through mechanisms that alter homing to the vein graft of graft-extrinsic cells, particularly leukocytes. CLINICAL RELEVANCE: The utility of autologous vein grafts is severely reduced by neointimal hyperplasia, which accelerates subsequent graft atherosclerosis. Our study demonstrates that vein graft neointimal hyperplasia is aggravated by activity of the cell-surface “CXC” chemokine receptor-4 (CXCR4), which is critical for recruitment of bone marrow-derived cells to sites of inflammation. Our model for CXCR4 deficiency used mice with heterozygous deficiency of Cxcr4. Consequently, our results suggest the possibility that a CXCR4 antagonist--like plerixafor, currently in clinical use--could be applied to vein grafts periadventitially, and perhaps achieve beneficial effects on vein graft neointimal hyperplasia.

Duke Scholars

Published In

J Vasc Surg

DOI

EISSN

1097-6809

Publication Date

November 2012

Volume

56

Issue

5

Start / End Page

1390 / 1397

Location

United States

Related Subject Headings

  • Veins
  • Signal Transduction
  • Receptors, CXCR4
  • Neointima
  • Mice, Inbred C57BL
  • Mice
  • Hyperplasia
  • Disease Progression
  • Cardiovascular System & Hematology
  • Animals
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Zhang, L., Brian, L., & Freedman, N. J. (2012). Vein graft neointimal hyperplasia is exacerbated by CXCR4 signaling in vein graft-extrinsic cells. J Vasc Surg, 56(5), 1390–1397. https://doi.org/10.1016/j.jvs.2012.03.254
Zhang, Lisheng, Leigh Brian, and Neil J. Freedman. “Vein graft neointimal hyperplasia is exacerbated by CXCR4 signaling in vein graft-extrinsic cells.J Vasc Surg 56, no. 5 (November 2012): 1390–97. https://doi.org/10.1016/j.jvs.2012.03.254.
Zhang L, Brian L, Freedman NJ. Vein graft neointimal hyperplasia is exacerbated by CXCR4 signaling in vein graft-extrinsic cells. J Vasc Surg. 2012 Nov;56(5):1390–7.
Zhang, Lisheng, et al. “Vein graft neointimal hyperplasia is exacerbated by CXCR4 signaling in vein graft-extrinsic cells.J Vasc Surg, vol. 56, no. 5, Nov. 2012, pp. 1390–97. Pubmed, doi:10.1016/j.jvs.2012.03.254.
Zhang L, Brian L, Freedman NJ. Vein graft neointimal hyperplasia is exacerbated by CXCR4 signaling in vein graft-extrinsic cells. J Vasc Surg. 2012 Nov;56(5):1390–1397.
Journal cover image

Published In

J Vasc Surg

DOI

EISSN

1097-6809

Publication Date

November 2012

Volume

56

Issue

5

Start / End Page

1390 / 1397

Location

United States

Related Subject Headings

  • Veins
  • Signal Transduction
  • Receptors, CXCR4
  • Neointima
  • Mice, Inbred C57BL
  • Mice
  • Hyperplasia
  • Disease Progression
  • Cardiovascular System & Hematology
  • Animals