title: Arhgef15 promotes retinal angiogenesis by mediating VEGF-induced Cdc42 activation and potentiating RhoJ inactivation in endothelial cells.
abstract: BACKGROUND
  Drugs inhibiting vascular endothelial growth factor (VEGF) signaling are globally administered to suppress deregulated angiogenesis in a variety of eye diseases. However, anti-VEGF therapy potentially affects the normal functions of retinal neurons and glias which constitutively express VEGF receptor 2. Thus, it is desirable to identify novel drug targets which are exclusively expressed in endothelial cells (ECs). Here we attempted to identify an EC-specific Rho guanine nucleotide exchange factor (GEF) and evaluate its role in retinal angiogenesis.
  
  
  RESULTS
  By exploiting fluorescence-activated cell sorting and microarray analyses in conjunction with in silico bioinformatics analyses, we comprehensively identified endothelial genes in angiogenic retinal vessels of postnatal mice. Of 9 RhoGEFs which were highly expressed in retinal ECs, we show that Arhgef15 acted as an EC-specific GEF to mediate VEGF-induced Cdc42 activation and potentiated RhoJ inactivation, thereby promoting actin polymerization and cell motility. Disruption of the Arhgef15 gene led to delayed extension of vascular networks and subsequent reduction of total vessel areas in postnatal mouse retinas.
  
  
  CONCLUSIONS
  Our study provides information useful to the development of new means of selectively manipulating angiogenesis without affecting homeostasis in un-targeted tissues; not only in eyes but also in various disease settings such as cancer.
authors.affiliation: Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Kobe, Japan.
authors.forename: Sentaro
authors.initials: S
authors.lastname: Kusuhara
authors.forename: Yoko
authors.initials: Y
authors.lastname: Fukushima
authors.forename: Shigetomo
authors.initials: S
authors.lastname: Fukuhara
authors.forename: Lars Martin
authors.initials: LM
authors.lastname: Jakt
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Okada
authors.forename: Yuri
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hata
authors.forename: Kohji
authors.initials: K
authors.lastname: Nishida
authors.forename: Akira
authors.initials: A
authors.lastname: Negi
authors.forename: Masanori
authors.initials: M
authors.lastname: Hirashima
authors.forename: Naoki
authors.initials: N
authors.lastname: Mochizuki
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Nishikawa
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Uemura
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D020411:Oligonucleotide Array Sequence Analysis; D055503:Protein Multimerization; D034622:RNA Interference; D012160:Retina / Q000166:cytology / Q000378:metabolism; D012171:Retinal Vessels / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D000199:Actins; C578514:ARHGEF15 protein, human; D020662:Guanine Nucleotide Exchange Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C417188:RHOJ protein, human; D020764:cdc42 GTP-Binding Protein; D020741:rho GTP-Binding Proteins