Loss of endothelial-ARNT in adult mice contributes to dampened circulating proangiogenic cells and delayed wound healing.
The recruitment and homing of circulating bone marrow-derived cells include endothelial progenitor cells (EPCs) that are critical to neovascularization and tissue regeneration of various vascular pathologies. We report here that conditional inactivation of hypoxia-inducible factor's (HIF) transcriptional activity in the endothelium of adult mice (Arnt(ΔiEC) mice) results in a disturbance of infiltrating cells, a hallmark of neoangiogenesis, during the early phases of wound healing. Cutaneous biopsy punches show distinct migration of CD31(+) cells into wounds of control mice by 36 hours. However, a significant decline in numbers of infiltrating cells with immature vascular markers, as well as decreased transcript levels of genes associated with their expression and recruitment, were identified in wounds of Arnt(ΔiEC) mice. Matrigel plug assays further confirmed neoangiogenic deficiencies alongside a reduction in numbers of proangiogenic progenitor cells from bone marrow and peripheral blood samples of recombinant vascular endothelial growth factor-treated Arnt(ΔiEC) mice. In addition to HIF's autocrine requirements in endothelial cells, our data implicate that extrinsic microenvironmental cues provided by endothelial HIF are pivotal for early migration of proangiogenic cells, including those involved in wound healing.
Case Cardiovascular Research Institute and University Hospitals Harrington Heart & Vascular Institute, Case Western Reserve University School of Medicine, Cleveland, OH, USA University of Rochester, School of Medicine and Dentistry, Rochester, NY, USA.
Yu
Y
Han
Case Cardiovascular Research Institute and University Hospitals Harrington Heart & Vascular Institute, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Jiayi
J
Tao
Case Cardiovascular Research Institute and University Hospitals Harrington Heart & Vascular Institute, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Alla
A
Gomer
Case Cardiovascular Research Institute and University Hospitals Harrington Heart & Vascular Institute, Case Western Reserve University School of Medicine, Cleveland, OH, USA dlr36@case.edu.
Diana L
DL
Ramirez-Bergeron
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002465:Cell Movement / Q000502:physiology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000502:physiology; D012867:Skin / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000166:cytology*; D014157:Transcription Factors / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*
D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A
ARNT; SDF-1; VEGF; endothelial precursor cells; hypoxia; neoangiogenesis; peripheral artery disease; vasculogenesis; wound healing