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 2

Arterial innervation correlates with netrin-1 expression.

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Arterial innervation correlates with netrin-1 expression. X-gal staining...
X-gal staining of Ntn1+/– tissues. (A) Note absence of blue netrin-1 staining in noninnervated P0 mesenteric arteries and (B) netrin-1 expression at P2 coincident with the onset of arterial innervation. (C–F) Arteries in the Circle of Willis start expressing netrin-1 at P2. Images in D and F show higher-magnification views of the boxed areas in C and E, respectively. (G) Adult skin arteries express netrin-1. (H) Resistance arteries branching off the femoral artery are netrin-1 positive. (I) Absence of netrin-1 expression in cardiac muscle and carotid arteries. (J) Iliac and femoral arteries do not express netrin-1. (K–M) Cryostat sections through the middle caudal artery show netrin-1 expression in anti-SMA+ SMCs. (N–P) Note absence of netrin-1 staining in SMCs of the carotid artery. V, vein. Scale bars: 200 μm (A, B, and H); 1 mm (D, F, G, and J); 2 mm (C, E, and I); 50 μm (K–M); 25 μm (N–P).