Netrin-1 controls sympathetic arterial innervation
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
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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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 4

DCC mediates sympathetic innervation in response to netrin-1.

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DCC mediates sympathetic innervation in response to netrin-1. (A) Anti-D...
(A) Anti-DCC immunostaining on TH+ SCG axons in vitro and sympathetic nerves surrounding mesenteric arteries in vivo. (B and C) Confocal images of P3 mesenteric arteries from Dccfl/fl TH-Cre control mice (B) and Dccfl/fl TH-Cre+ mice (C) injected with 4-OHT at P0, P1, and P2 and stained with anti-TH and anti-SMA antibodies. (D and E) Quantification of mesenteric artery innervation in Dccfl/fl TH-Cre control mice and Dccfl/fl TH-Cre+ mice shown in B and C and in mice injected with PBS vehicle or an anti-DCC function-blocking antibody (2.5 μg/g, intraperitoneal injection at P1 and P2). Innervation in control littermates was set as 1. All measurements were made by an observer blinded to the experimental condition (n = 6 [E] and 3 [D] mice per group; 8–10 images per mesentery). ***P < 0.0001, unpaired 2-tailed t test. Scale bars: 50 μm (A, top row, B, and C); 10 μm (A, bottom row).