Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability.
The angiogenic sprout has been compared to the growing axon, and indeed, many proteins direct pathfinding by both structures. The Roundabout (Robo) proteins are guidance receptors with well-established functions in the nervous system; however, their role in the mammalian vasculature remains ill defined. Here we show that an endothelial-specific Robo, Robo4, maintains vascular integrity. Activation of Robo4 by Slit2 inhibits vascular endothelial growth factor (VEGF)-165-induced migration, tube formation and permeability in vitro and VEGF-165-stimulated vascular leak in vivo by blocking Src family kinase activation. In mouse models of retinal and choroidal vascular disease, Slit2 inhibited angiogenesis and vascular leak, whereas deletion of Robo4 enhanced these pathologic processes. Our results define a previously unknown function for Robo receptors in stabilizing the vasculature and suggest that activating Robo4 may have broad therapeutic application in diseases characterized by excessive angiogenesis and/or vascular leak.
Jones
Christopher A
CA
Department of Oncological Sciences, University of Utah, 15 North 2030 East, Salt Lake City, Utah 84112, USA.
London
Nyall R
NR
Chen
Haoyu
H
Park
Kye Won
KW
Sauvaget
Dominique
D
Stockton
Rebecca A
RA
Wythe
Joshua D
JD
Suh
Wonhee
W
Larrieu-Lahargue
Frederic
F
Mukouyama
Yoh-Suke
YS
Lindblom
Per
P
Seth
Pankaj
P
Frias
Antonio
A
Nishiya
Naoyuki
N
Ginsberg
Mark H
MH
Gerhardt
Holger
H
Zhang
Kang
K
Li
Dean Y
DY
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002829:Choroid / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012171:Retinal Vessels / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C467484:VEGFA protein, human