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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. 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 ?+ 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.

SUBMITTER: Motegi S

PROVIDER: S-EPMC3184509 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Pericyte-derived MFG-E8 regulates pathologic angiogenesis.

Motegi Sei-ichiro S Leitner Wolfgang W WW Lu Michael M Tada Yayoi Y Sárdy Miklós M Wu Chuanjin C Chavakis Triantafyllos T Udey Mark C MC

Arteriosclerosis, thrombosis, and vascular biology 20110707 9

<h4>Objective</h4>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.<h4>Methods and results</h4>We used knockout mice ...[more]

PMID: 21737783

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Project description:Brain accumulation of amyloid-beta (Aβ) is a crucial feature in Alzheimer´s disease (AD) and cerebral amyloid angiopathy (CAA), although the pathophysiological relationship between these diseases remains unclear. Numerous proteins are associated with Aβ deposited in parenchymal plaques and/or cerebral vessels. We hypothesized that the study of these proteins would increase our understanding of the overlap and biological differences between these two pathologies and may yield new diagnostic tools and specific therapeutic targets. We used a laser capture microdissection approach combined with mass spectrometry in the APP23 transgenic mouse model of cerebral-β-amyloidosis to specifically identify vascular Aβ-associated proteins. We focused on one of the main proteins detected in the Aβ-affected cerebrovasculature: MFG-E8 (milk fat globule-EGF factor 8), also known as lactadherin. We first validated the presence of MFG-E8 in mouse and human brains. Immunofluorescence and immunoblotting studies revealed that MFG-E8 brain levels were higher in APP23 mice than in WT mice. Furthermore, MFG-E8 was strongly detected in Aβ-positive vessels in human postmortem CAA brains, whereas MFG-E8 was not present in parenchymal Aβ deposits. Levels of MFG-E8 were additionally analysed in serum and cerebrospinal fluid (CSF) from patients diagnosed with CAA, patients with AD and control subjects. Whereas no differences were found in MFG-E8 serum levels between groups, MFG-E8 concentration was significantly lower in the CSF of CAA patients compared to controls and AD patients. Finally, in human vascular smooth muscle cells MFG-E8 was protective against the toxic effects of the treatment with the Aβ40 peptide containing the Dutch mutation. In summary, our study shows that MFG-E8 is highly associated with CAA pathology and highlights MFG-E8 as a new CSF biomarker that could potentially be used to differentiate cerebrovascular Aβ pathology from parenchymal Aβ deposition.

Dataset Information

Pericyte-derived MFG-E8 regulates pathologic angiogenesis.

Publications

Pericyte-derived MFG-E8 regulates pathologic angiogenesis.

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