Netrins are secreted molecules with roles in axonal growth and angiogenesis. The Netrin receptor UNC5B is required during embryonic development for vascular patterning, suggesting that it may also contribute to postnatal and pathological angiogenesis. Here we show that unc5b is down-regulated in quiescent adult vasculature, but re-expressed during sprouting angiogenesis in matrigel and tumor implants. Stimulation of UNC5B-expressing neovessels with an agonist (Netrin-1) inhibits sprouting angiogenesis. Genetic loss of function of unc5b reduces Netrin-1-mediated angiogenesis inhibition. Expression of UNC5B full-length receptor also triggers endothelial cell repulsion in response to Netrin-1 in vitro, whereas a truncated UNC5B lacking the intracellular signaling domain fails to induce repulsion. These data show that UNC5B activation inhibits sprouting angiogenesis, thus identifying UNC5B as a potential anti-angiogenic target.[Keywords: Vessel guidance; axon guidance molecules; tip cell; neovascularization; tumor angiogenesis] Supplemental material is available at http://www.genesdev.org. Three members of the netrin gene family, netrin-1, netrin-3, and ␤-netrin/netrin-4, have been identified in mammals (Serafini et al. 1996;Van Raay et al. 1997;Wang et al. 1999;Koch et al. 2000;Yin et al. 2000). Netrins are bifunctional guidance cues, attracting some axons while repelling others (Dickson 2002). Netrin-1 is secreted from cells at the ventral midline of the central nervous system and attracts commissural axons toward the midline. Netrins can, however, also repel certain axons, including the trochlear motor axons in vertebrates (Colamarino and Tessier-Lavigne 1995). Attraction and repulsion are mediated via activation of receptors of the deleted in colorectal cancer (DCC) and uncoordinated 5 (UNC5) families, respectively. The DCC family consists of DCC and Neogenin Keino-Masu et al. 1996), while the UNC5 family comprises four members, UNC5A to UNC5D (Leung-Hagesteijn et al. 1992;Leonardo et al. 1997). Axon attraction is mediated by the DCC receptors (Fazeli et al. 1997), while repulsion requires signaling through UNC5-DCC receptor heterodimers or UNC5 receptor homodimers (Hedgecock et al. 1990;Hong et al. 1999;Keleman and Dickson 2001).In addition to their role in axon guidance, Netrins and their receptors have been implicated in other develop- Article is online at http://www.genesdev.org/cgi

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Recent data suggest that angiotensin II AT1 receptor antagonists may be beneficial in the treatment of atherosclerosis. To clarify how AT1 receptor antagonists reduce atherosclerosis, the effect of irbesartan on atherosclerotic lesion development was determined in low-fat, chow-fed apolipoprotein (Apo) E-deficient mice. Irbesartan (50 mg/kg per day) strongly decreased lesion development after a 12-week treatment period (lesion size: irbesartan treated, 20,524 +/- 4,200 microm(2) vs. control, 99,600 +/- 14,500; 79.4% inhibition, p < 0.001). This effect was not due to an effect of irbesartan on lipoprotein levels because irbesartan slightly increased total cholesterol levels and decreased the ratio of Apo A-I relative to Apo B levels. Immunochemical analysis of the atherosclerotic lesions using the mac3 monoclonal antibody showed the presence of macrophages in the lesions of control mice, whereas sections from irbesartan-treated animals only showed occasional labeling in the lesion area. These data suggest that irbesartan inhibits monocyte/macrophage influx into the vessel wall. Therefore, expression levels of monocyte chemoattractant protein-1 (MCP-1), as well as other chemokines involved in macrophage infiltration into the lesion area, were measured in the aortic sinus of control and irbesartan-treated animals. Irbesartan treatment strongly decreased MCP-1 mRNA levels as well as MCP-1 immunostaining in the lesion area. This effect of irbesartan on MCP-1 occurred without an effect on CCR2, the receptor of MCP-1. Expression of macrophage inflammatory protein (MIP)-1alpha, another CC chemokine expressed in atherosclerotic lesions, was also reduced after irbesartan treatment, without effect on CCR3 and CCR5, the receptors of MIP-1alpha. Concomitantly, the expression of the angiogenic chemokines KC and MIP-2, which are functionally related to interleukin-8, were downregulated, whereas their shared receptor CXCR2 was upregulated. These data suggest that inhibition of the inflammatory component of lesion progression plays an important role in the inhibitory effect of AT1 receptor antagonists on atherosclerotic lesion formation.