Autonomic sympathetic axons extend along and innervate resistance arteries to control vascular tone and participate in blood pressure regulation. In this issue of the JCI, Brunet and colleagues reveal that sympathetic innervation of arteries is facilitated by secretion of the axon guidance molecule netrin-1 by arterial VSMCs. Furthermore, disruption of the signaling cascade induced by netrin-1 through its receptor DCC resulted in defective arterial innervation and sympathetic control of vasoconstriction. This comprehensive study represents a major step forward in our understanding of the coordinated wiring of the vascular and nervous systems in various tissues.
(A) Vascular-derived signals, such as artemin, NT-3, NGF, and ETs, guide sympathetic axon extension along mesenteric arteries. Sympathetic innervation of mesenteric arteries develops after the axons have connected with the gut and the alignment of sympathetic nerves and mesenteric arteries has been established. There are two possible models to explain how sympathetic axons project both to the gut and mesenteric arteries, as illustrated in B and C. (B) The “interstitial branches for innervation” model suggests that VSMC-derived netrin-1 triggers established sympathetic nerves to form interstitial branches for arterial innervation. (C) The “late-born neurons for innervation” model suggests that there are two distinct sets of sympathetic axons that project either to the gut or the mesenteric arteries, and the axons that selectively project to the mesenteric arteries develop at a relatively late embryonic stage compared with the axons that project to the gut.