Diet-induced obesity drives negative mouse vein graft wall remodeling

Abstract

Introduction: The heightened inflammatory phenotype associated with obesity has been linked to the development of cardiovascular diseases. Short-term high-fat feeding induces a proinflammatory state that may impact the blood vessel wall. CD11c, a significantly increased dendritic cell biomarker during diet-induced obesity (DIO), may have a mechanistic role in this high-fat feeding effect. We hypothesized that the proinflammatory effect of short-term DIO accelerates vein bypass graft failure via CD11c-dependent mechanisms.

Methods: Male 9-week-old DIO mice (n = 13, C57BL/6J recipients; n = 6, CD11c(-/-) recipients) and normal chow controls (n = 15, C57BL/6J recipients; n = 6, CD11c(-/-) recipients) underwent unilateral carotid interposition vein isografting (inferior vena cava from the same diet and genetic background donor), with a midgraft or outflow focal stenosis. Vein grafts were harvested at either 1 week (immunohistochemical staining for early CD11c expression) or 4 weeks later (morphometric analyses and CD11c evaluation).

Results: Despite a 40% larger body size, C57BL/6J DIO mice had 44% smaller poststenosis vein graft lumens (P = .03) than their controls via an acceleration of overall negative vein graft wall remodeling in the day-28 midgraft focal stenosis model but not in the outflow stenosis model. Higher CD11c expression occurred in DIO midgraft-stenosis vein graft walls, both at postoperative days 7 and 28. In contrast, with in vivo CD11c deficiency, DIO did not elicit this poststenotic negative remodeling but attenuated intimal hyperplasia.

Conclusions: These findings highlight negative wall remodeling as a potential factor leading to vein graft failure and provide direct evidence that short-term dietary alterations in the mammalian metabolic milieu can have lasting implications related to acute vascular interventions. DIO induces negative mouse vein graft wall remodeling via CD11c-depedent pathways.

Copyright © 2014 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Figures

Fig 1

Weight curves of vein grafted mice (C57BL/6J or CD11c−/−), with 60 kcal% high-fat diet (DIO) or 10 kcal% standard chow (Normal). Values are shown as mean ± SEM.

Fig 2

Serial crosssectional analysis of vein graft (midgraft portion) wall adaptation in C57BL/6J (A–E) and CD11c−/− (F–J), normal chow vs. DIO mouse midgraft focal stenosis model. A,F: Mean calculated lumen area. B,G: Mean IEL perimeter. C,H: Mean intima thickness. D,I: Mean media+adventitia thickness. E,J: Mean intima/(media+adventitia) thickness ratio. Values were shown as means ± SEM. * P<.05 and ** P<.01 vs. the same location of vein graft in normal chow counterpart mice. K–N: Representative Masson’s trichrome stained images at 400 μm distal to midgraft focal stenosis (D400). K: C57 Normal; L: C57 DIO; M: CD11c−/− Normal; N: CD11c−/− DIO. Three hand-drawn black lines in each image delineate the boundaries of different layers of vein graft wall. From the lumen to the outside: lumen boundary, internal elastic lamina, and outside boundary. Scale bar = 200 μm.

Fig 3

Morphologic analysis of vein graft wall adaptation with outflow focal stenosis, in C57BL/6J normal chow vs. DIO mice. A, Mean calculated lumen area. B, Mean IEL perimeter. C: Mean intima thickness. D, Mean media+adventitia thickness. E, Mean intima/(media+adventitia) thickness ratio. Values were shown as means ± SEM.

Fig 4

The representative CD11c immunohistochemical images and the quantitative analysis of midgraft stenotic vein graft wall in C57BL/6J normal chow vs. DIO mice. Day-7 vein grafts were acetone fixed and cryosectioned; day-28 grafts were formalin fixed and citrate buffer prepared. Note the brown membrane labeling of irregular-shaped cells mainly in the adventitial or adjacent soft tissue of vein graft wall. Scale bars = 50 μm. * P<.05 vs. C57 normal chow mice at the same time point.