Netrin-1 controls sympathetic arterial innervation
Isabelle Brunet, … , Holger Eltzschig, Anne Eichmann
Isabelle Brunet, … , Holger Eltzschig, Anne Eichmann
Published June 17, 2014
Citation Information: J Clin Invest. 2014;124(7):3230-3240. https://doi.org/10.1172/JCI75181.
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Research Article

Netrin-1 controls sympathetic arterial innervation

Abstract

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.

Authors

Isabelle Brunet, Emma Gordon, Jinah Han, Brunella Cristofaro, Dong Broqueres-You, Chun Liu, Karine Bouvrée, Jiasheng Zhang, Raquel del Toro, Thomas Mathivet, Bruno Larrivée, Julia Jagu, Laurence Pibouin-Fragner, Luc Pardanaud, Maria J.C. Machado, Timothy E. Kennedy, Zhen Zhuang, Michael Simons, Bernard I. Levy, Marc Tessier-Lavigne, Almut Grenz, Holger Eltzschig, Anne Eichmann

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Figure 5

Innervation of peripheral resistance arteries in adult Ntn1-deficient mice.

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Innervation of peripheral resistance arteries in adult Ntn1-deficient mi...
(A–F) Confocal microscopy shows (A and D) normal innervation of skin arterioles in Ntn1fl/fl Sm22-Cre– and wild-type mice, while TH+ fibers are present but fail to contact the arterioles (B and C) in Ntn1fl/fl Sm22-Cre+ and (E and F) Ntn1+/– skin. (G–I) Anti-TH staining of microdissected iliac and femoral arteries and side branches from adult (G and H) wild-type and (I) Ntn1+/– mice. Images in H and I were taken of the femoral artery; right panels in H and I show a higher-magnification images of resistance arteries. (I) Note normal femoral artery innervation in Ntn1+/– mice but reduction of resistance artery innervation. (J–M) Transmission electron microscopy images from mesenteric arteries of wild-type and Ntn1+/– mice. SM, SMC; el, EEL; V, varicosity. (N–P) Similar innervation of arteries in the Circle of Willis in wild-type mice, Ntn1+/– mice, and Ntn1+/– mice treated with an anti–netrin-1 function-blocking antibody (BlAb; 20 μg/g, intraperitoneal injection at P12, P15, and P18; analysis at P20). Scale bars: 50 μm (A–F, left panels; H and I, right panels; and N–P); 10 μm (A–F, right panels); 100 μm (H and I, left panels); 1 μm (J–M); 2 mm (G).