title: Skin graft vascularization involves precisely regulated regression and replacement of endothelial cells through both angiogenesis and vasculogenesis.
abstract: BACKGROUND
  Long-term survival of a skin graft is dependent on eventual revascularization. The authors' aim in the present study was to determine whether skin graft vascularization occurs by (1) simple reconnection of vessels, (2) ingrowth of recipient vasculature, (3) outgrowth of donor-derived vessels, and/or (4) recruitment of bone marrow-derived endothelial progenitor cells.
  
  
  METHODS
  Full-thickness skin grafts (1 x 1 cm) were transferred between wild-type FVB/N mice (n = 20) and transgenic tie2/lacZ mice (n = 20), where lacZ expression is controlled by the endothelial specific tie2 promoter, allowing differentiation of recipient and donor endothelial cells. The contribution of endothelial progenitor cells to skin graft neovascularization was determined using a bone marrow transplant model where tie2/lacZ bone marrow was transplanted into wild-type mice (n = 20).
  
  
  RESULTS
  Vascular regression in the graft was observed at the periphery starting on day 3 and moving centrally through day 21, sparing graft vessels in the absolute center of the graft. At the same time, vascular ingrowth occurred from the wound bed to replace the regressing vessels. Furthermore, bone marrow-derived endothelial progenitor cells contributed to these new vessels starting as early as day 7. Surprisingly, the contribution of bone marrow-derived vessels to the overall process was approximately 15 to 20 percent of new endothelial cells.
  
  
  CONCLUSIONS
  Replacement of the donor graft vasculature by endothelial and endothelial progenitor cells from the recipient along preexisting channels is the predominant mechanism for skin graft revascularization. This mechanism is likely similar for all nonvascularized free grafts and suggests novel strategies for optimizing the vascularization of tissue constructs engineered in vitro.
authors.affiliation: Laboratory of Microvascular Research and Vascular Tissue Engineering, Institute of Reconstructive Plastic Surgery, New York University Medical Center, New York, NY, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Capla
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Ceradini
authors.forename: Oren M
authors.initials: OM
authors.lastname: Tepper
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Callaghan
authors.forename: Kirit A
authors.initials: KA
authors.lastname: Bhatt
authors.forename: Robert D
authors.initials: RD
authors.lastname: Galiano
authors.forename: Jamie P
authors.initials: JP
authors.lastname: Levine
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Gurtner
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000502:physiology*; D042787:Receptor, TIE-2 / Q000502:physiology; D016038:Skin Transplantation / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D042787:Receptor, TIE-2; D001616:beta-Galactosidase