title: Perivascular innate immune events modulate early murine vein graft adaptations.
abstract: OBJECTIVE
  Innate immunity drives numerous cardiovascular pathologies. Vein bypass grafting procedures are frequently accompanied by low-grade wound contamination. We hypothesized that a peri-graft innate immune challenge, via an outside-in route, augments inflammatory responses, which subsequently drive a component of negative vein graft wall adaptations; moreover, adipose tissue mediates this immune response.
  
  
  METHODS
  The inferior vena cava from a donor mouse was implanted into the common carotid artery of a recipient mouse utilizing a validated cuff technique (9-week-old male C57BL/6J mice). Slow-release low-dose (5 μg) lipopolysaccharide (LPS) (n = 9) or vehicle (n = 9) was applied peri-graft; morphologic analysis was completed (day 28). In parallel, vein-grafted mice received peri-graft LPS (n = 12), distant subcutaneous LPS (n = 6), or vehicle (n = 12), then day-1 and -3 harvest of grafts and adipose tissue for cytokines and toll-like receptor (TLR) signaling mRNA expression (qRT-PCR).
  
  
  RESULTS
  All recipient mice survived, and all vein grafts were patent. Acute low-dose local LPS challenge enhanced vein graft lumen loss (P = .04) and tended to augment intimal hyperplasia (P = .06). The surgical trauma of vein grafting universally upregulated key pro- and anti-inflammatory mediators within the day-1 graft wall, but varied on TLR signaling gene expression. Local and distant LPS accentuated these patterns until at least postoperative day 3. LPS challenge enhanced the inflammatory response in adipose tissue (locally > distantly); local LPS upregulated adipose TLR-4 dramatically.
  
  
  CONCLUSIONS
  Perivascular and distant inflammatory challenges potentiate the magnitude and duration of inflammatory responses in the early vein graft wall, negatively modulating wall adaptations, and thus, potentially contribute to vein graft failure. Furthermore, surgery activates innate immunity in adipose tissue, which is augmented (regionally > systemically) by LPS. Modulation of these local and distant inflammatory signaling networks stands as a potential strategy to enhance the durability of vascular interventions such as vein grafts.
authors.affiliation: Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Binh T
authors.initials: BT
authors.lastname: Nguyen
authors.forename: Peng
authors.initials: P
authors.lastname: Yu
authors.forename: Ming
authors.initials: M
authors.lastname: Tao
authors.forename: Shuai
authors.initials: S
authors.lastname: Hao
authors.forename: Tianyu
authors.initials: T
authors.lastname: Jiang
authors.forename: C Keith
authors.initials: CK
authors.lastname: Ozaki
mesh_terms: D000222:Adaptation, Physiological; D000273:Adipose Tissue / Q000276:immunology; D000818:Animals; D017536:Carotid Artery, Common / Q000276:immunology / Q000601:surgery; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006085:Graft Survival; D006965:Hyperplasia; D007113:Immunity, Innate; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D058017:Vascular Grafting; D014682:Vena Cava, Inferior / Q000276:immunology* / Q000473:pathology / Q000637:transplantation*
chemical_list: D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051193:Toll-Like Receptors