title: Pericyte-derived MFG-E8 regulates pathologic angiogenesis.
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.
  
  
  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.
  
  
  CONCLUSIONS
  These studies strongly implicate MFG-E8 in pericyte/pericyte precursor function and indicate that MFG-E8-directed therapeutics may merit further development.
authors: Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20802-1908, USA.
authors: Sei-ichiro
authors: S
authors: Motegi
authors: Wolfgang W
authors: WW
authors: Leitner
authors: Michael
authors: M
authors: Lu
authors: Yayoi
authors: Y
authors: Tada
authors: Miklós
authors: M
authors: Sárdy
authors: Chuanjin
authors: C
authors: Wu
authors: Triantafyllos
authors: T
authors: Chavakis
authors: Mark C
authors: MC
authors: Udey
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000502:physiology*; D002465:Cell Movement; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008894:Milk Proteins; D009389:Neovascularization, Pathologic / Q000209:etiology*; D020286:Pericytes / Q000378:metabolism*; D012164:Retinal Diseases / Q000209:etiology
chemical_list: D000954:Antigens, Surface; C490919:Mfge8 protein, mouse; D008894:Milk Proteins