Larrivée Bruno, Freitas Catarina, Trombe Marc, Lv Xiang, Delafarge Benjamin, Yuan Li, Bouvrée Karine, Bréant Christiane, Del Toro Raquel, Bréchot Nicolas, Germain Stéphane, Bono Françoise, Dol Frédérique, Claes Filip, Fischer Christian, Autiero Monica, Thomas Jean-Léon, Carmeliet Peter, Tessier-Lavigne Marc, Eichmann Anne
Institut National de la Santé et de la Recherche Médicale U833, F-75005 Paris, France.
Genes Dev. 2007 Oct 1;21(19):2433-47. doi: 10.1101/gad.437807.
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.
Netrins是在轴突生长和血管生成中起作用的分泌分子。Netrin受体UNC5B在胚胎发育期间对血管模式形成是必需的，这表明它也可能有助于出生后和病理性血管生成。在这里，我们表明unc5b在静止的成年脉管系统中下调，但在基质胶和肿瘤植入物中的发芽血管生成过程中重新表达。用激动剂（Netrin-1）刺激表达UNC5B的新生血管会抑制发芽血管生成。unc5b的基因功能丧失会降低Netrin-1介导的血管生成抑制作用。UNC5B全长受体的表达在体外也会触发内皮细胞对Netrin-1的排斥反应，而缺乏细胞内信号结构域的截短UNC5B则无法诱导排斥反应。这些数据表明UNC5B激活会抑制发芽血管生成，从而将UNC5B确定为潜在的抗血管生成靶点。
