title: Dynamics of angiogenesis during wound healing: a coupled in vivo and in silico study.
abstract: OBJECTIVE
  The most critical determinant of restoration of tissue structure during wound healing is the re-establishment of a functional vasculature, which largely occurs via angiogenesis, specifically endothelial sprouting from the pre-existing vasculature.
  
  
  METHODS
  We used confocal microscopy to capture sequential images of perfused vascular segments within the injured panniculus carnosus muscle in the mouse dorsal skin-fold window chamber to quantify a range of microcirculatory parameters during the first nine days of healing. This data was used to inform a mathematical model of sequential growth of the vascular plexus. The modeling framework mirrored the experimental circular wound domain and incorporated capillary sprouting and endothelial cell (EC) sensing of vascular endothelial growth factor gradients.
  
  
  RESULTS
  Wound areas, vessel densities and vessel junction densities obtained from the corresponding virtual wound were in excellent agreement both temporally and spatially with data measured during the in vivo healing process. Moreover, by perturbing the proliferative ability of ECs in the mathematical model, this leads to a severe reduction in vascular growth and poor healing. Quantitative measures from this second set of simulations were found to correlate extremely well with experimental data obtained from animals treated with an agent that targets endothelial proliferation (TNP-470).
  
  
  CONCLUSIONS
  Our direct combination and comparison of in vivo longitudinal analysis (over time in the same animal) and mathematical modeling employed in this study establishes a useful new paradigm. The virtual wound created in this study can be used to investigate a wide range of experimental hypotheses associated with wound healing, including disorders characterized by aberrant angiogenesis (e.g., diabetic models) and the effects of vascular enhancing/disrupting agents or therapeutic interventions such as hyperbaric oxygen.
authors.affiliation: Centre for Molecular Biosciences, University of Ulster, Coleraine, UK.
authors.forename: Maria J C
authors.initials: MJ
authors.lastname: Machado
authors.forename: Michael G
authors.initials: MG
authors.lastname: Watson
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Devlin
authors.forename: Mark A J
authors.initials: MA
authors.lastname: Chaplain
authors.forename: Steven R
authors.initials: SR
authors.lastname: McDougall
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003198:Computer Simulation; D042783:Endothelial Cells / Q000166:cytology; D066298:In Vitro Techniques; D008137:Longitudinal Studies; D051379:Mice; D008833:Microcirculation / Q000502:physiology; D018613:Microscopy, Confocal / Q000379:methods; D018482:Muscle, Skeletal / Q000098:blood supply; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010477:Perfusion; D014945:Wound Healing / Q000502:physiology*