title: A critical role for macrophages in neovessel formation and the development of stenosis in tissue-engineered vascular grafts.
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 CD11b-diphtheria 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.
authors.affiliation: Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Narutoshi
authors.initials: N
authors.lastname: Hibino
authors.forename: Tai
authors.initials: T
authors.lastname: Yi
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Duncan
authors.forename: Animesh
authors.initials: A
authors.lastname: Rathore
authors.forename: Ethan
authors.initials: E
authors.lastname: Dean
authors.forename: Yuji
authors.initials: Y
authors.lastname: Naito
authors.forename: Alan
authors.initials: A
authors.lastname: Dardik
authors.forename: Themis
authors.initials: T
authors.lastname: Kyriakides
authors.forename: Joseph
authors.initials: J
authors.lastname: Madri
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Pober
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Shinoka
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Breuer
mesh_terms: D000818:Animals; D001705:Bioprosthesis / Q000009:adverse effects; D001807:Blood Vessel Prosthesis / Q000009:adverse effects*; D003251:Constriction, Pathologic / Q000517:prevention & control; D005260:Female; D008264:Macrophages / Q000473:pathology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D023822:Tissue Engineering; D054457:Tissue Scaffolds