Endothelial cell-specific FGD5 involvement in vascular pruning defines neovessel fate in mice.
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.


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(CIP1) levels in aging mice.


CONCLUSIONS
We have identified FGD5 as a novel genetic regulator of vascular pruning by activation of endothelial cell-targeted apoptosis.
Molecular Cardiology Laboratory, Ee2389a, Thoraxcenter, Erasmus University Medical Center, Gravendijkwal 230, 3015 GE Rotterdam, Netherlands.
Caroline
C
Cheng
Remco
R
Haasdijk
Dennie
D
Tempel
Esther H M
EH
van de Kamp
Robert
R
Herpers
Frank
F
Bos
Wijnand K
WK
Den Dekker
Lau A J
LA
Blonden
Renate
R
de Jong
Petra E
PE
Bürgisser
Ihsan
I
Chrifi
Erik A L
EA
Biessen
Stefanie
S
Dimmeler
Stefan
S
Schulte-Merker
Henricus J
HJ
Duckers
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control*; D012164:Retinal Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059467:Transcriptome / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; C572072:FGD5 protein, human; C574715:FGD5 protein, mouse; D020662:Guanine Nucleotide Exchange Factors