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The vasculature is innervated by a network of peripheral afferents that sense and regulate blood flow. Here, we describe a system of non-peptidergic sensory neurons with cell bodies in the spinal ganglia that regulate vascular tone in the distal arteries. We identify a population of mechanosensitive neurons, marked by tropomyosin receptor kinase C (TrkC) and tyrosine hydroxylase in the dorsal root ganglia, which projects to blood vessels. Local stimulation of TrkC neurons decreases vessel diameter and blood flow, whereas systemic activation increases systolic blood pressure and heart rate variability via the sympathetic nervous system. Ablation of the neurons provokes variability in local blood flow, leading to a reduction in systolic blood pressure, increased heart rate variability, and ultimately lethality within 48 h. Thus, a population of TrkC + sensory neurons forms part of a sensory-feedback mechanism that maintains cardiovascular homeostasis through the autonomic nervous system., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 European Molecular Biology Laboratory. Published by Elsevier Inc. All rights reserved.)

Diabetes mellitus (DM) is a major global health concern, affecting more than 9% of the world population. The most common complication of DM is diabetic peripheral neuropathy (DPN), which leads to neuropathic pain in as many as 50% of patients. Despite its prevalence, there is neither good prevention of nor treatments for DPN, representing a major gap in care for the many who are afflicted. It has long been known from patient studies that both small and large primary afferent fibers undergo structural changes in DPN; however, the exact functional contributions of these changes to DPN symptomology are unknown, necessitating animal studies. This review first presents the commonly used mouse models of DPN resulting from both type 1 and type 2 DM. It then discusses structural changes in Aβ, Aδ, and C fibers throughout the progression of DPN and their respective contributions to painful DPN in both human patients and DM mouse models. Finally, it highlights remaining questions on sensory neuron structure-function relationships in painful DPN and how we may address these in mouse models by using technological advances in cell-specific modulation. Only when these structure-function relationships are understood, can novel targeted therapeutics be developed for DPN.