A neurovascular survival axis for adult sympathetic neurons

Adult neuronal survival underlies lifelong brain function, yet its sustaining mechanisms remain unclear. We identify a neurovascular survival axis at intracranial arteries in mice, where superior cervical ganglion (SCG) sympathetic terminals form synapse-like neurosmooth muscular junctions (NsMJs) with arterial smooth muscle cells (aSMCs) that secrete netrin-4 (Ntn4). Adult aSMC-restricted Ntn4 deletion selectively reduces rostral, intracranial-projecting (cerebrospinal fluid-traced) SCG neurons; the denervation of the intracranial arterial plexus follows soma loss. Local recombinant Ntn4 delivery to the SCG rescues these phenotypes. Ntn4 withdrawal engages a receptor-interacting serine/threonine kinase 1 (RIPK1)/mixed lineage kinase domain-like pseudokinase (MLKL)-linked, caspase-independent, non-inflammatory death program via deleted in colorectal cancer (DCC): unliganded DCC triggers neuronal loss, whereas Dcc knockout preserves vulnerable neurons. Arterial Ntn4 declines from young adulthood and precedes selective neuronal attrition before midlife; aSMC-targeted Ntn4 overexpression prevents this loss. Together, intracranial arteries provide a local, non-cell-autonomous trophic niche that maintains this adult sympathetic subset and becomes compromised as vascular Ntn4 output wanes with age.