Endothelial cell-specific fgd5 involvement in vascular pruning defines neovessel fate in mice

Caroline Cheng, Remco Haasdijk, Dennie Tempel, Esther H.M. Van De Kamp, Robert Herpers, Frank Bos, Wijnand K. Den Dekker, Lau A.J. Blonden, Renate De Jong, Petra E. Bürgisser, Ihsan Chrifi, Erik A.L. Biessen, Stefanie Dimmeler, Stefan Schulte-Merker, Henricus J. Duckers

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)

Abstract

Background-New vessel formation contributes to organ development during embryogenesis and tissue repair in response to mechanical damage, inflammation, and ischemia in adult organisms. Early angiogenesis includes formation of an excessive primitive network that needs to be reorganized into a secondary vascular network with higher hierarchical structure. Vascular pruning, the removal of aberrant neovessels by apoptosis, is a vital step in this process. Although multiple molecular pathways for early angiogenesis have been identified, little is known about the genetic regulators of secondary network development. Methods and Results-Using a transcriptomics approach, we identified a new endothelial specific gene named FYVE, RhoGEF, and PH domain-containing 5 (FGD5) that plays a crucial role in vascular pruning. Loss-and gain-of-function studies demonstrate that FGD5 inhibits neovascularization, indicated by in vitro tube-formation, aortic-ring, and coated-bead assays and by in vivo coated-bead plug assays and studies in the murine retina model. FGD5 promotes apoptosis-induced vaso-obliteration via induction of the hey1-p53 pathway by direct binding and activation of cdc42. Indeed, FGD5 correlates with apoptosis in endothelial cells during vascular remodeling and was linked to rising p21 levels in aging mice. Conclusion-We have identified FGD5 as a novel genetic regulator of vascular pruning by activation of endothelial cell-targeted apoptosis.

Original languageEnglish
Pages (from-to)3142-3158
Number of pages17
JournalCirculation
Volume125
Issue number25
DOIs
Publication statusPublished - 26 Jun 2012
Externally publishedYes

Keywords

  • angiogenesis-inducing agents
  • apoptosis
  • endothelium
  • FGD5
  • models, animal

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