Tie2-dependent knockout of HIF-1 impairs burn wound vascularization and homing of bone marrow-derived angiogenic cells.
OBJECTIVE
Hypoxia-inducible factor 1 (HIF-1) is a heterodimer composed of HIF-1α and HIF-1β subunits. HIF-1 is known to promote tissue vascularization by activating the transcription of genes encoding angiogenic factors, which bind to receptors on endothelial cells (ECs) and bone marrow-derived angiogenic cells (BMDACs). In this study, we analysed whether HIF-1 activity in the responding ECs and BMDACs is also required for cutaneous vascularization during burn wound healing.


RESULTS
We generated mice with floxed alleles at the Hif1a or Arnt locus encoding HIF-1α and HIF-1β, respectively. Expression of Cre recombinase was driven by the Tie2 gene promoter, which is expressed in ECs and bone marrow cells. Tie2Cre(+) and Tie2Cre(-) mice were subjected to burn wounds of reproducible diameter and depth. Deficiency of HIF-1α or HIF-1β in Tie2-lineage cells resulted in delayed wound closure, reduced vascularization, decreased cutaneous blood flow, impaired BMDAC mobilization, and decreased BMDAC homing to burn wounds.


CONCLUSIONS
HIF-1 activity in Tie2-lineage cells is required for the mobilization and homing of BMDACs to cutaneous burn wounds and for the vascularization of burn wound tissue.
Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Kakali
K
Sarkar
Sergio
S
Rey
Xianjie
X
Zhang
Raul
R
Sebastian
Guy P
GP
Marti
Karen
K
Fox-Talbot
Amanda V
AV
Cardona
Junkai
J
Du
Yee Sun
YS
Tan
Lixin
L
Liu
Frank
F
Lay
Frank J
FJ
Gonzalez
John W
JW
Harmon
Gregg L
GL
Semenza
D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics*; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000473:pathology; D002056:Burns / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D055786:Gene Knockout Techniques; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D042787:Receptor, TIE-2; D012867:Skin / Q000098:blood supply / Q000293:injuries / Q000473:pathology; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*
C497397:Arnt protein, mouse; D017931:DNA Primers; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse