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 1

Sympathetic arterial innervation in mice occurs after birth.

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Sympathetic arterial innervation in mice occurs after birth. (A–J) Confo...
(A–J) Confocal microscopy of mesenteric arteries stained with anti-SMA and anti-TH antibodies. (A and B) Note no arterial innervation at P0, (E and F) beginning of innervation at P2 (arrows), and (I and J) full innervation at P10. High-magnification images show (C and D) axon bundles crossing over the artery at P0 but absence of individual fibers, (G and H) whereas single sympathetic fiber growth cones contact the artery wall at P2 (asterisks). (K–P) Cryostat section of mesenteric arteries at P0, P3, and P10 stained with indicated markers. Elastin staining showed arterial maturation, (N) with internal elastic lamina (IEL, white arrowheads) present at P3 (L) but not at P0, and (P) the EEL (yellow arrowheads) forming at P10. SMA immunostaining shows 1 layer of SMCs at P0, and 2 layers at P3 and P10. (M) TH+ sympathetic fibers start contacting arteries at P3 (arrows), and (O) their density increased by P10 (arrows). (K, M, and O) Sympathetic nerve bundles aligned with arteries were visible at P0, P3, and P10 (asterisks). (Q–S) Scanning electronic microscopy of mesenteric arteries at P0, P3, and P10. Nerve bundles (asterisks) are present at P0 and P3. Boxes show (R) a P3 sympathetic axon contacting SMC extensions and (S) a P10 axon contacting a SMC through the EEL. A, artery; EC, endothelial cell. Scale bars: 50 μm (A, B, E, F, I, and J); 10 μm (C, D, G, H, and Q); 25 μm (K–P); 20 μm (R and S); 1 μm (inset in R and S).