Pericyte-derived MFG-E8 regulates pathologic angiogenesis

Sei Ichiro Motegi, Wolfgang W. Leitner, Michael Lu, Yayoi Tada, Miklós Sárdy, Chuanjin Wu, Triantafyllos Chavakis, Mark C. Udey

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2024-2034
Number of pages11
JournalArteriosclerosis, thrombosis, and vascular biology
Volume31
Issue number9
DOIs
StatePublished - Sep 2011

Keywords

  • MFG-E8
  • angiogenesis
  • melanoma
  • oxygen-induced retinopathy
  • pericyte

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