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 6

Defective vasoconstriction in Ntn1smko and Ntn1+/– mice.

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Defective vasoconstriction in Ntn1smko and Ntn1+/– mice. (A) Laser-Doppl...
(A) Laser-Doppler recordings of blood flow in the paws of anesthetized mice monitored for body core temperature. Red color denotes highest blood flow. Note vasoconstriction in Ntn1fl/fl Sm22-Cre– and in wild-type control mice between 36.9°C and 36.6°C, but absence of vasoconstriction in the Ntn1smko or Ntn1+/– littermates (n = 5 mice per group for Ntn1fl/fl Sm22-Cre– and Cre+ and n = 6 mice per group for Ntn1+/+ and Ntn1+/–). (B) Laser-Doppler quantification of vasoconstriction in control littermates and Ntn1smko and Ntn1+/– mice. At 37.8°C, the foot blood flow was not significantly different between all experimental groups. For each animal, the measurement of foot blood flow at 37.8°C was considered as 100%, and the data of foot blood flow at other temperatures were expressed as the percentages of the measurement at 37.8°C. ***P < 0.001, 2-way ANOVA followed by Bonferroni post test. Prazosin treatment (1 mg/kg, intraperitoneal injection 30 minutes prior to the onset of the experiment) abolishes vasoconstriction in both Ntn1+/– mice and wild-type littermates.