title: Vascular endothelial growth factor is important for brown adipose tissue development and maintenance.
abstract: Vascular endothelial growth factor (VEGF) is critical for angiogenesis, but also has pleiotropic effects on several nonvascular cells. Our aim was to investigate the role of VEGF in brown adipose tissue (BAT). We show that VEGF expression increases 2.5-fold during differentiation of cultured murine brown adipocytes and that VEGF receptor-2 is phosphorylated, indicating VEGF signaling. VEGF increased proliferation in brown preadipocytes in vitro by 70%, and blockade of VEGF signaling using anti-VEGFR2 antibody DC101 increased brown adipocyte apoptosis, as determined by cell number and activation of caspase 3. Systemic VEGF neutralization in mice, accomplished by adenoviral expression of soluble Flt1, resulted in 7-fold increase in brown adipocyte apoptosis, mitochondrial degeneration, and increased mitophagy compared to control mice expressing a null adenovirus. Absence of the heparan sulfate-binding VEGF isoforms, VEGF164 and VEGF188, resulted in abnormal BAT development in mice at E15.5, with fewer brown adipocytes and lower mitochondrial protein compared to wild-type littermates. These results suggest a role for VEGF in brown adipocytes and preadipocytes to promote survival, proliferation, and normal mitochondria and development.
authors.affiliation: Department of Pathology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Mandrita
authors.initials: M
authors.lastname: Bagchi
authors.forename: Leo A
authors.initials: LA
authors.lastname: Kim
authors.forename: Jeremie
authors.initials: J
authors.lastname: Boucher
authors.forename: Tony E
authors.initials: TE
authors.lastname: Walshe
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: Patricia A
authors.initials: PA
authors.lastname: D'Amore
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D015870:Gene Expression; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D053148:Caspase 3
keywords: apoptosis; mitochondria; proliferation; sFlt1