Brunet Isabelle, Gordon Emma, Han Jinah, Cristofaro Brunella, Broqueres-You Dong, Liu Chun, Bouvrée Karine, Zhang Jiasheng, del Toro Raquel, Mathivet Thomas, Larrivée Bruno, Jagu Julia, Pibouin-Fragner Laurence, Pardanaud Luc, Machado Maria J C, Kennedy Timothy E, Zhuang Zhen, Simons Michael, Levy Bernard I, Tessier-Lavigne Marc, Grenz Almut, Eltzschig Holger, Eichmann Anne
J Clin Invest. 2014 Jul;124(7):3230-40. doi: 10.1172/JCI75181. Epub 2014 Jun 17.
Autonomic sympathetic nerves innervate peripheral resistance arteries, thereby regulating vascular tone and controlling blood supply to organs. Despite the fundamental importance of blood flow control, how sympathetic arterial innervation develops remains largely unknown. Here, we identified the axon guidance cue netrin-1 as an essential factor required for development of arterial innervation in mice. Netrin-1 was produced by arterial smooth muscle cells (SMCs) at the onset of innervation, and arterial innervation required the interaction of netrin-1 with its receptor, deleted in colorectal cancer (DCC), on sympathetic growth cones. Function-blocking approaches, including cell type-specific deletion of the genes encoding Ntn1 in SMCs and Dcc in sympathetic neurons, led to severe and selective reduction of sympathetic innervation and to defective vasoconstriction in resistance arteries. These findings indicate that netrin-1 and DCC are critical for the control of arterial innervation and blood flow regulation in peripheral organs.
自主交感神经支配外周阻力动脉，从而调节血管张力并控制器官的血液供应。尽管血流控制至关重要，但交感神经对动脉的支配是如何发育的在很大程度上仍不清楚。在这里，我们确定轴突导向因子netrin-1是小鼠动脉神经支配发育所需的关键因素。Netrin-1在神经支配开始时由动脉平滑肌细胞（SMC）产生，并且动脉神经支配需要netrin-1与其受体——在结直肠癌中缺失（DCC）的蛋白——在交感神经生长锥上相互作用。功能阻断方法，包括细胞类型特异性敲除平滑肌细胞中编码Ntn1的基因和交感神经元中编码Dcc的基因，导致交感神经支配严重且选择性地减少，以及阻力动脉中血管收缩功能缺陷。这些发现表明，netrin-1和DCC对于外周器官中动脉神经支配的控制和血流调节至关重要。
