Mouse anti-Human UNC5B monoclonal antibody, clone 2B0

Blood vessels and nerves are structurally similar complex branched systems. Their guidance must be exquisitely regulated to ensure proper wiring of both networks. Recent results showed that specialized endothelial cells, resembling axonal growth cones, form the tips of growing capillaries. These endothelial tip cells guide outgrowing capillaries in response to gradients of extracellular matrix-bound vascular endothelial growth factor. Several axon guidance molecules, including Semaphorins, Netrins, Ephrins and Slits, have also been implicated in vessel pathfinding and network formation. In particular, Semaphorin3E and its receptor plexinD1 in addition to the Netrin receptor UNC5B have recently been shown to direct endothelial tip cell navigation.

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.