Netrin-1 controls sympathetic arterial innervation

J Clin Invest. 2014 Jul;124(7):3230-40. doi: 10.1172/JCI75181. Epub 2014 Jun 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • DCC Receptor
  • Female
  • Growth Cones / physiology
  • Male
  • Mesenteric Arteries / growth & development
  • Mesenteric Arteries / innervation*
  • Mesenteric Arteries / physiology
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Models, Neurological
  • Myocytes, Smooth Muscle / physiology
  • Nerve Growth Factors / deficiency
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / physiology*
  • Netrin-1
  • Pregnancy
  • Receptors, Cell Surface / physiology
  • Sympathetic Nervous System / growth & development
  • Sympathetic Nervous System / physiology*
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / physiology*
  • Vasoconstriction / physiology

Substances

  • DCC Receptor
  • Dcc protein, mouse
  • Nerve Growth Factors
  • Ntn1 protein, mouse
  • Receptors, Cell Surface
  • Tumor Suppressor Proteins
  • Netrin-1