TY - JOUR
T1 - Pericyte-derived MFG-E8 regulates pathologic angiogenesis
AU - Motegi, Sei Ichiro
AU - Leitner, Wolfgang W.
AU - Lu, Michael
AU - Tada, Yayoi
AU - Sárdy, Miklós
AU - Wu, Chuanjin
AU - Chavakis, Triantafyllos
AU - Udey, Mark C.
PY - 2011/9
Y1 - 2011/9
N2 - Objective-: MFG-E8 (also called lactadherin and SED1) is a secreted glycoprotein that has been previously implicated in enhancement of vascular endothelial growth factor-dependent angiogenesis. Major sources of MFG-E8 in vivo and precise mechanisms of MFG-E8 action remain undetermined. The objective of this study was to identify important sources of MFG-E8 in vivo and further elucidate the role(s) of MFG-E8 in the regulation of angiogenesis. Methods and results-: We used knockout mice and anti-MFG-E8 antibodies to study MFG-E8 function in vivo. In melanomas and in retinas of mice with oxygen-induced retinopathy, MFG-E8 colocalized with pericytes rather than endothelial cells, and platelet-derived growth factor receptor β+ pericytes/pericyte precursors purified from tumors contained large amounts of MFG-E8 mRNA. Tumor-and retinopathy-associated angiogenesis was diminished in MFG-E8 knockout mice, and pericyte coverage of neovessels was reduced. Inhibition of MFG-E8 production by 10T1/2 cells (surrogate pericyte/pericyte precursors) using small interfering RNAs and short hairpin RNAs, or inhibition of MFG-E8 action with some anti-MFG-E8 antibodies, selectively attenuated migration in vitro. Significantly, the anti-MFG-E8 antibodies that inhibited 10T1/2 cell migration in vitro also inhibited pathological angiogenesis in vivo. Conclusion-: These studies strongly implicate MFG-E8 in pericyte/pericyte precursor function and indicate that MFG-E8-directed therapeutics may merit further development.
AB - Objective-: MFG-E8 (also called lactadherin and SED1) is a secreted glycoprotein that has been previously implicated in enhancement of vascular endothelial growth factor-dependent angiogenesis. Major sources of MFG-E8 in vivo and precise mechanisms of MFG-E8 action remain undetermined. The objective of this study was to identify important sources of MFG-E8 in vivo and further elucidate the role(s) of MFG-E8 in the regulation of angiogenesis. Methods and results-: We used knockout mice and anti-MFG-E8 antibodies to study MFG-E8 function in vivo. In melanomas and in retinas of mice with oxygen-induced retinopathy, MFG-E8 colocalized with pericytes rather than endothelial cells, and platelet-derived growth factor receptor β+ pericytes/pericyte precursors purified from tumors contained large amounts of MFG-E8 mRNA. Tumor-and retinopathy-associated angiogenesis was diminished in MFG-E8 knockout mice, and pericyte coverage of neovessels was reduced. Inhibition of MFG-E8 production by 10T1/2 cells (surrogate pericyte/pericyte precursors) using small interfering RNAs and short hairpin RNAs, or inhibition of MFG-E8 action with some anti-MFG-E8 antibodies, selectively attenuated migration in vitro. Significantly, the anti-MFG-E8 antibodies that inhibited 10T1/2 cell migration in vitro also inhibited pathological angiogenesis in vivo. Conclusion-: These studies strongly implicate MFG-E8 in pericyte/pericyte precursor function and indicate that MFG-E8-directed therapeutics may merit further development.
KW - MFG-E8
KW - angiogenesis
KW - melanoma
KW - oxygen-induced retinopathy
KW - pericyte
UR - http://www.scopus.com/inward/record.url?scp=80052148658&partnerID=8YFLogxK
U2 - 10.1161/ATVBAHA.111.232587
DO - 10.1161/ATVBAHA.111.232587
M3 - Article
C2 - 21737783
AN - SCOPUS:80052148658
SN - 1079-5642
VL - 31
SP - 2024
EP - 2034
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 9
ER -