Robo4 Maintains Vessel Integrity and Inhibits Angiogenesis by Interacting with UNC5B

被引：175

作者：

Koch, Alexander W. ^{[1
]}

Mathivet, Thomas ^{[2
]}

Larrivee, Bruno ^{[2
]}

Tong, Raymond K. ^{[1
]}

Kowalski, Joe ^{[1
]}

Pibouin-Fragner, Laurence ^{[2
]}

Bouvree, Karine ^{[2
]}

Stawicki, Scott ^{[1
]}

Nicholes, Katrina ^{[1
]}

Rathore, Nisha ^{[1
]}

Scales, Suzie J. ^{[1
]}

Luis, Elizabeth ^{[1
]}

del Toro, Raquel ^{[2
]}

Freitas, Catarina ^{[2
]}

Breant, Christiane ^{[2
]}

Michaud, Annie ^{[2
]}

Corvol, Pierre ^{[2
]}

Thomas, Jean-Leon ^{[3
]}

Wu, Yan ^{[1
]}

Peale, Franklin ^{[1
]}

Watts, Ryan J. ^{[1
]}

Tessier-Lavigne, Marc ^{[1
]}

Bagri, Anil ^{[1
]}

Eichmann, Anne ^{[2
]}

机构：

[1] Genentech Inc, San Francisco, CA 94030 USA

[2] Coll France, INSERM, U833, F-75005 Paris, France

[3] UPMC, INSERM, UMR S 975, CNRS,UMR 7225,Hop Salpetriere, F-75013 Paris, France

来源：

DEVELOPMENTAL CELL | 2011年 / 20卷 / 01期

关键词：

GUIDANCE RECEPTORS; NETRIN RECEPTORS; AXON GUIDANCE; SLIT; PROTEINS; BINDING; LYMPHANGIOGENESIS; PERMEABILITY; ACTIVATION; ROUNDABOUT;

D O I：

10.1016/j.devcel.2010.12.001

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Robo4 is an endothelial cell-specific member of the Roundabout axon guidance receptor family. To identify Robo4 binding partners, we performed a protein-protein interaction screen with the Robo4 extracellular domain. We find that Robo4 specifically binds to UNC5B, a vascular Netrin receptor, revealing unexpected interactions between two endothelial guidance receptors. We show that Robo4 maintains vessel integrity by activating UNC5B, which inhibits signaling downstream of vascular endothelial growth factor (VEGF). Function-blocking monoclonal antibodies against Robo4 and UNC5B increase angiogenesis and disrupt vessel integrity. Soluble Robo4 protein inhibits VEGF-induced vessel permeability and rescues barrier defects in Robo4(-/-) mice, but not in mice treated with anti-UNC5B. Thus, Robo4-UNC5B signaling maintains vascular integrity by counteracting VEGF signaling in endothelial cells, identifying a novel function of guidance receptor interactions in the vasculature.

引用

页码：33 / 46

页数：14

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