title: The temporal and spatial development of vascularity in a healing displaced fracture.
abstract: Underlying vascular disease is an important pathophysiologic factor shared among many co-morbid conditions associated with poor fracture healing, such as diabetes, obesity, and age. Determining the temporal and spatial patterns of revascularization following a fracture is essential for devising therapeutic strategies to augment this critical reparative process. Seminal studies conducted in the last century have investigated the pattern of vascularity in bone following a fracture. The consensus model culminating from these classical studies depicts a combination of angiogenesis emanating from both the intact intramedullary and periosteal vasculature. Subsequent to the plethora of experimental fracture angiography in the early to mid-20th century there has been a paucity of reports describing the pattern of revascularization of a healing fracture. Consequently the classical model of revascularization of a displaced fracture has remained largely unchanged. Here, we have overcome the limitations of animal fracture models performed in the above described classical studies by combining novel techniques of bone angiography and a reproducible murine femur fracture model to demonstrate for the first time the complete temporal and spatial pattern of revascularization in a displaced/stabilized fracture. These studies were designed specifically to i) validate the classical model of fracture revascularization of a displaced/stabilized fracture, ii) assess the association between intramedullary and periosteal angiogenesis and iii) elucidate the expression of VEGF/VEGF-R in relation to the classical model. From the studies, in conjunction with classic studies of angiogenesis during fracture repair, we propose a novel model (see abstract graphic) that defines the process of bone revascularization subsequent to injury to guide future approaches to enhance fracture healing. This new model validates and advances the classical model by providing evidence that during the process of revascularization of a displaced fracture 1) periosteal angiogenesis occurs in direct communication with the remaining intact intramedullary vasculature as a result of a vascular shunt and 2) vascular union occurs through an intricate interplay between intramembranous and endochondral VEGF/VEGF-R mediated angiogenesis.
authors.affiliation: Vanderbilt University Medical Center, Department of Orthopaedics, 2200 Children's Way, Nashville, TN 37232-9565, USA; Tokyo Medical and Dental University, Department of Orthopaedic and Spinal Surgery, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Yuasa
authors.affiliation: Vanderbilt University Medical Center, Department of Orthopaedics, 2200 Children's Way, Nashville, TN 37232-9565, USA; Vanderbilt University Medical Center, Department of Pathology, C-2314 Medical Center North, Nashville, TN 37232-2561, USA.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Mignemi
authors.affiliation: Vanderbilt University Medical Center, Department of Pharmacology, 438 Robinson Research Building, Nashville, TN 37232-6600, USA.
authors.forename: Joey V
authors.initials: JV
authors.lastname: Barnett
authors.affiliation: Vanderbilt University Medical Center, Department of Pathology, C-2314 Medical Center North, Nashville, TN 37232-2561, USA.
authors.forename: Justin M M
authors.initials: JM
authors.lastname: Cates
authors.affiliation: Vanderbilt University Medical Center, Department of Orthopaedics, 2200 Children's Way, Nashville, TN 37232-9565, USA; Vanderbilt University Medical Center, Center for Bone Biology, 1255 MRB IV, Nashville, TN 37232-9565, USA.
authors.forename: Jeffry S
authors.initials: JS
authors.lastname: Nyman
authors.affiliation: Tokyo Medical and Dental University, Department of Orthopaedic and Spinal Surgery, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Okawa
authors.affiliation: Tokyo Medical and Dental University, Department of Orthopaedic and Spinal Surgery, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Yoshii
authors.affiliation: Vanderbilt University Medical Center, Department of Orthopaedics, 2200 Children's Way, Nashville, TN 37232-9565, USA; Vanderbilt University Medical Center, Department of Pathology, C-2314 Medical Center North, Nashville, TN 37232-2561, USA.
authors.forename: Herbert S
authors.initials: HS
authors.lastname: Schwartz
authors.affiliation: Vanderbilt University Medical Center, Department of Orthopaedics, 2200 Children's Way, Nashville, TN 37232-9565, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Stutz
authors.affiliation: Vanderbilt University Medical Center, Department of Orthopaedics, 2200 Children's Way, Nashville, TN 37232-9565, USA; Vanderbilt University Medical Center, Department of Pathology, C-2314 Medical Center North, Nashville, TN 37232-2561, USA; Vanderbilt University Medical Center, Department of Pharmacology, 438 Robinson Research Building, Nashville, TN 37232-6600, USA; Vanderbilt University Medical Center, Center for Bone Biology, 1255 MRB IV, Nashville, TN 37232-9565, USA; Vanderbilt University Medical Center, Department of Pediatrics, 2200 Children's Way, Nashville, TN 37232-9565, USA. Electronic address: Jon.Schoenecker@vanderbilt.edu.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Schoenecker
mesh_terms: D000792:Angiography; D000818:Animals; D005264:Femoral Fractures / Q000000981:diagnostic imaging; D017102:Fracture Healing / Q000502:physiology*; D051379:Mice; D008856:Microscopy, Fluorescence; D018919:Neovascularization, Physiologic / Q000502:physiology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: Angiogenesis; Angiography; Bone vascularity; Fracture healing; Non-union; Vascular endothelial growth factor