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In their Matters Arising article, McMullan et al. (2022) offer alternative explanations for the phenotypes we observed upon stimulation and ablation of TrkCCreERT2-positive neurons in mice. Their interpretations are focused on two aspects: first, whether the vasoconstriction we observed upon activation of TrkCCreERT2 neurons is really mediated by TrkC/TH-positive neurons, or whether it might stem from stimulation of somatic nociceptors that also express TrkC; and second, whether the lethality observed after ablation of TrkCCreERT2 neurons might be a result of ablation of vagal afferents and not TrkC/TH neurons located in the spinal ganglia. Central to both of these concerns is the expression and recombination efficiency of the TrkCCreERT2 transgene in these other cell types. This Matters Arising Response paper addresses the McMullan et al. (2022) Matters Arising paper, published concurrently in Cell Reports. • The TrkCCreERT2 BAC transgene does not fully reproduce the expression pattern of TrkC • Cre-mediated recombination is absent in nociceptors and sympathetic or vagal ganglia • Vasoconstriction is likely mediated by TrkC+/TH+ DRG neurons and not nociceptors • Strategies targeting only TrkC+/TH+ DRG neurons are required to understand lethality Heppenstall et al. demonstrate that the absence of TrkC-CreERT2-mediated recombination in nociceptors or sympathetic or vagal ganglia suggest that it is TrkC+/TH+ DRG neurons that regulate cardiovascular parameters. [ABSTRACT FROM AUTHOR]

In their Matters Arising article, McMullan et al. (2022) offer alternative explanations for the phenotypes we observed upon stimulation and ablation of TrkC CreERT2 -positive neurons in mice. Their interpretations are focused on two aspects: first, whether the vasoconstriction we observed upon activation of TrkC CreERT2 neurons is really mediated by TrkC/TH-positive neurons, or whether it might stem from stimulation of somatic nociceptors that also express TrkC; and second, whether the lethality observed after ablation of TrkC CreERT2 neurons might be a result of ablation of vagal afferents and not TrkC/TH neurons located in the spinal ganglia. Central to both of these concerns is the expression and recombination efficiency of the TrkC CreERT2 transgene in these other cell types. This Matters Arising Response paper addresses the McMullan et al. (2022) Matters Arising paper, published concurrently in Cell Reports., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

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. [Display omitted] • TrkC+/Th+ DRG neurons project to blood vessels • Local stimulation of TrkC+ DRG neurons decreases vessel diameter and blood flow • Systemic activation of TrkC+ DRG neurons increases blood pressure and heart rate • Ablation of TrkC+ neurons dysregulates cardiovascular homeostasis and is lethal Morelli et al. identify a subpopulation of peripheral sensory neurons marked by TrkC and Th that projects to distal blood vessels. They demonstrate that these neurons regulate peripheral perfusion, blood pressure, and heart rate. [ABSTRACT FROM AUTHOR]