Transcriptional activation of hypoxia-inducible factor-1 (HIF-1) in myeloid cells promotes angiogenesis through VEGF and S100A8.
Emerging evidence indicates that myeloid cells are essential for promoting new blood vessel formation by secreting various angiogenic factors. Given that hypoxia-inducible factor (HIF) is a critical regulator for angiogenesis, we questioned whether HIF in myeloid cells also plays a role in promoting angiogenesis. To address this question, we generated a unique strain of myeloid-specific knockout mice targeting HIF pathways using human S100A8 as a myeloid-specific promoter. We observed that mutant mice where HIF-1 is transcriptionally activated in myeloid cells (by deletion of the von Hippel-Lindau gene) resulted in erythema, enhanced neovascularization in matrigel plugs, and increased production of vascular endothelial growth factor (VEGF) in the bone marrow, all of which were completely abrogated by either genetic or pharmacological inactivation of HIF-1. We further found that monocytes were the major effector producing VEGF and S100A8 proteins driving neovascularization in matrigel. Moreover, by using a mouse model of hindlimb ischemia we observed significantly improved blood flow in mice intramuscularly injected with HIF-1-activated monocytes. This study therefore demonstrates that HIF-1 activation in myeloid cells promotes angiogenesis through VEGF and S100A8 and that this may become an attractive therapeutic strategy to treat diseases with vascular defects.
Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, Korea.
G-One
GO
Ahn
Jun
J
Seita
Beom-Ju
BJ
Hong
Young-Eun
YE
Kim
Seoyeon
S
Bok
Chan-Ju
CJ
Lee
Kwang Soon
KS
Kim
Jerry C
JC
Lee
Nicholas J
NJ
Leeper
John P
JP
Cooke
Hak Jae
HJ
Kim
Il Han
IH
Kim
Irving L
IL
Weissman
J Martin
JM
Brown
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D040501:Calgranulin A / Q000378:metabolism*; D003094:Collagen; D003433:Crosses, Genetic; D017931:DNA Primers / Q000235:genetics; D004338:Drug Combinations; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006614:Hindlimb / Q000098:blood supply; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007511:Ischemia / Q000503:physiopathology; D007797:Laminin; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011509:Proteoglycans; D015533:Transcriptional Activation / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D040501:Calgranulin A; D017931:DNA Primers; D004338:Drug Combinations; D051793:Hypoxia-Inducible Factor 1; D007797:Laminin; D011509:Proteoglycans; C086145:S100a8 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen