Expression of vascular endothelial growth factor receptor 1 in bone marrow-derived mesenchymal cells is dependent on hypoxia-inducible factor 1.
Bone marrow-derived cells are recruited to sites of ischemia, where they promote tissue vascularization. This response is dependent upon the expression of vascular endothelial growth factor (VEGF) receptor 1 (VEGFR1), which mediates cell migration in response to VEGF or placental growth factor (PLGF). In this study, we found that exposure of cultured mouse bone marrow-derived mesenchymal stromal cells (MSC) to hypoxia or an adenovirus encoding a constitutively active form of hypoxia-inducible factor 1 (HIF-1) induced VEGFR1 mRNA and protein expression and promoted ex vivo migration in response to VEGF or PLGF. MSC in which HIF-1 activity was inhibited by a dominant negative or RNA interference approach expressed markedly reduced levels of VEGFR1 and failed to migrate or activate AKT in response to VEGF or PLGF. Thus, loss-of-function and gain-of-function approaches demonstrated that HIF-1 activity is necessary and sufficient for basal and hypoxia-induced VEGFR1 expression in bone marrow-derived MSC.
Vascular Biology Program, Institute for Cell Engineeringe, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Hiroaki
H
Okuyama
Balaji
B
Krishnamachary
Yi Fu
YF
Zhou
Hideko
H
Nagasawa
Marta
M
Bosch-Marce
Gregg L
GL
Semenza
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D015687:Cell Hypoxia; D002465:Cell Movement; D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis* / Q000235:genetics*
C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D040281:Vascular Endothelial Growth Factor Receptor-1