A critical role for macrophages in neovessel formation and the development of stenosis in tissue-engineered vascular grafts

Narutoshi Hibino, Tai Yi, Daniel R. Duncan, Animesh Rathore, Ethan Dean, Yuji Naito, Alan Dardik, Themis Kyriakides, Joseph Madri, Jordan S. Pober, Toshiharu Shinoka, Christopher K. Breuer

Research output: Contribution to journalArticlepeer-review

Abstract

The primary graft-related complication during the first clinical trial evaluating the use of tissue-engineered vascular grafts (TEVGs) was stenosis. We investigated the role of macrophages in the formation of TEVG stenosis in a murine model. We analyzed the natural history of TEVG macrophage infiltration at critical time points and evaluated the role of cell seeding on neovessel formation. To assess the function of infiltrating macrophages, we implanted TEVGs into mice that had been macrophage depleted using clodronate liposomes. To confirm this, we used a CD11bdiphtheria toxin-receptor (DTR) transgenic mouse model. Monocytes infiltrated the scaffold within the first few days and initially transformed into M1 macrophages. As the scaffold degraded, the macrophage infiltrate disappeared. Cell seeding decreased the incidence of stenosis (32% seeded, 64% unseeded, P=0.024) and the degree of macrophage infiltration at 2 wk. Unseeded TEVGs demonstrated conversion from M1 to M2 phenotype, whereas seeded grafts did not. Clodronate and DTR inhibited macrophage infiltration and decreased stenosis but blocked formation of vascular neotissue, evidenced by the absence of endothelial and smooth muscle cells and collagen. These findings suggest that macrophage infiltration is critical for neovessel formation and provides a strategy for predicting, detecting, and inhibiting stenosis in TEVGs.

Original languageEnglish (US)
Pages (from-to)4253-4263
Number of pages11
JournalFASEB Journal
Volume25
Issue number12
DOIs
StatePublished - Dec 2011
Externally publishedYes

Keywords

  • Clodronate liposomes
  • Monocytes

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

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