A vagal-to-sympathetic reflex controls lung vascular leak
Authors: E. Robinson, E. M. Ibanez, B. Santibanez Ocampo, J. Li, N. Ballal, J. M. Miller, K. Shivdikar, B. D. Umans, S. L. Prescott
Abstract
Dynamic regulation of the vascular barrier is required for an effective inflammatory response, allowing delivery of plasma proteins and immune cells to sites of insult. Although normally protective, sustained leak becomes costly in organs like the lung, where swelling stiffens tissue and impairs breathing, yet many upstream regulators remain unidentified. Using a chemogenetic screen of vagal afferent subtypes, we identify a neural reflex that drives lung vascular leak. The reflex originates in an orphan population of neurons expressing Cysltr2 that innervates alveolar capillary beds and senses both mechanical and inflammatory stimuli, fitting classic definitions of pulmonary 'J' receptors, an afferent subtype described anatomically since the 1950s whose function has remained speculative. Activating CYSLTR2 neurons increases lung vascular leak within minutes and causes perivascular edema and respiratory dysfunction, whereas silencing them during inhaled allergen challenge reduces leak and improves lung mechanics. Rather than acting locally through antidromic peptide release, this reflex engages brainstem relays and sympathetic efferents to broadcast its effects throughout lung vasculature. Vagal control of the vascular barrier thus forms an axis of organ defense that can go awry in disease, revealing new ways to regulate organ fluid balance upstream of the endothelium
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Peripheral and Central Neuroinflammatory Mechanisms Regulating Vagal Sensory Circuit Processing and Cough in Lung DiseaseStuart B. Mazzone, Alexandria K. Driessen, N. Verzele · 2026 · Neuroimmunomodulation · Not summarized yet
This review discusses vagal sensory processing and cough in lung disease, whereas the paper tests a vagal reflex regulating pulmonary vascular leak.
Abstract
Abstract Background The pulmonary system can be exposed to a diverse range of injurious insults which drive pathological events including inflammation, tissue damage, and structural remodelling within the airways and lungs. Summary Patients with lung inflammation and injury often experience sensory neurological complications, suggesting that the pathological processes in the lung either impact or extend into the nervous system. Key Messages Cough is a common presenting neurological symptom in patients with lung disease and there is growing evidence that neuroinflammation, either within the vagal nerves innervating the airways and lungs or within the central sensory neural circuits regulating…
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Neural Mechanisms of Heart–Lung Crosstalk in Chronic Heart FailureJuan Hong, Samuel Gillman, P. Pellegrino et al. · 2026 · Circulation Research · Not summarized yet
This study examines cardiac and pulmonary afferent reflexes in heart failure, while the paper identifies a vagal-to-sympathetic reflex controlling lung vascular leak.
Abstract
Background: The cardiac sympathetic afferent reflex (CSAR) and pulmonary spinal afferent reflex (PSAR) amplify sympathetic activity and may contribute to chronic heart failure (CHF). We hypothesized that cardiac injury triggers a cardiac nerve-mediated cytokine uptake cascade that propagates neural inflammation in thoracic dorsal root ganglia (DRGs) to drive reciprocal cardiopulmonary afferent sensitization through suppression of voltage-gated potassium (Kv) channels after myocardial infarction (MI). Method: MI was induced in rats by coronary ligation. Molecular profiling, immunofluorescence, tissue clearing, and functional assays were used to assess neuroinflammation and reflex responses. R…
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TRPV3 drives lung injury by sensing inflammatory signals to disrupt alveolar epithelial barrier and promote inflammation.Chu-Chu Xi, Fang Zhao, Lin Li et al. · 2026 · British Journal of Pharmacology · Not summarized yet
This study tests TRPV3-mediated disruption of the alveolar epithelial barrier during lung injury, rather than neural regulation of vascular permeability.
Abstract
BACKGROUND AND PURPOSE Pulmonary inflammation is a central pathological feature of many respiratory diseases. Transient receptor potential vanilloid 3 (TRPV3), a non-selective cation channel abundantly expressed in the skin, nerve and lung tissues, is involved in itch, skin inflammation and barrier regulation. However, its function in the pulmonary system remains elusive. We aimed to determine whether and how TRPV3 is involved in pulmonary inflammation. EXPERIMENTAL APPROACH Lipopolysaccharide (LPS) and carvacrol were used to model acute lung injury (ALI) in C57BL/6J mice. Histology, bronchoalveolar lavage fluid analysis, qPCR, Western blotting, immunofluorescence, Ca2+ imaging, transepithel…
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Electrophysiological properties of the dorsal motor nucleus of the vagus motoneurones controlling airway mucus secretion in rats.D. P. de Souza, Renato W. Martins Sá, Luiza Henrique de Souza et al. · 2026 · Journal of Physiology · Not summarized yet
This study characterizes vagal motor neurons controlling airway mucus secretion, whereas the paper examines sensory neurons and sympathetic control of lung vascular leak.
Abstract
The parasympathetic efferent innervation to the respiratory airways controls bronchoconstriction and mucus secretion. It is known that the parasympathetic respiratory motoneurones (PRMNs) projecting to the airways are located in the nucleus ambiguus (NA) and dorsal motor nucleus of the vagus (DMV). Although NA PRMNs are known to regulate bronchoconstriction in both physiological and pathological conditions, the electrophysiological properties of DMV PRMNs and their functional role in regulating the airways are not entirely clear. Retrograde labelling, neuronal and ventilatory recordings, optogenetics, chemogenetics, and histological and molecular analyses in vitro and in vivo preparations of…
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The dorsal vagal complex harbors a constitutively immune-enriched microglial populationS. Gaigé, R. Barbouche, Alain Tonetto et al. · 2026 · Frontiers in Neuroanatomy · Not summarized yet
This study examines immune-enriched microglia in the dorsal vagal complex, a brainstem hub relevant to the neural pathways studied in the paper.
Abstract
The dorsal vagal complex (DVC) comprises three anatomically and functionally linked structures, the area postrema, the nucleus tractus solitarius, and the dorsal motor nucleus of the vagus nerve, forming a key hub for the integration of peripheral inflammatory information. These structures play a unique role at the neuroimmune interface, conveying peripheral immune signals to the brain and generating behavioral and physiological responses through two complementary pathways: a neural pathway, via vagal afferents projecting to the nucleus tractus solitarius, and a humoral pathway, via the area postrema, which lacks a blood–brain barrier and is therefore sensitive to circulating inflammatory me…
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The Role of the Nervous System in Lung DiseaseC. Mawer, A. Patel, N. Zeltner et al. · 2026 · Current Neurology and Neuroscience Reports · Not summarized yet
This review surveys sensory and autonomic regulation of pulmonary physiology and disease, including neural mechanisms relevant to lung vascular leak.
Abstract
Peripheral nerves regulate pulmonary physiology in a nerve-type- and compartment-specific manner through neurotransmitters, neurotrophins and axon-guidance cues. This review examines how sensory and autonomic pathways influence pulmonary homeostasis and disease, and evaluates the experimental models available to investigate these interactions. Dysregulated pulmonary innervation has been implicated in acute lung injury, airway hyperresponsiveness, pulmonary fibrosis and lung cancer, where neural signals may modulate immune activation, stromal remodelling and tumour progression. However, pulmonary neurobiology remains comparatively underexplored, in part because neuronal cell bodies are locate…
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Crucial role of TRPV2 in the development of hypoxia-induced pulmonary hypertensionK. Nakamura, S. Akagi, Y. Saito et al. · 2026 · European Heart Journal · Not summarized yet
This study investigates TRPV2-dependent hypoxic vasoconstriction and pulmonary vascular remodeling, rather than neural control of vascular leak.
Abstract
Sustained hypoxia induces pulmonary vasoconstriction, leading to adverse pulmonary vascular remodeling and pulmonary hypertension (PH). However, the precise mechanism by which vasoconstriction leads to vascular remodeling remains to be elucidated. Transient receptor potential cation channel subfamily V member 2 (TRPV2) is a component of native Ca2+-permeable cation channels and a mechanosensor that responds to membrane stretch in vascular smooth muscles. We hypothesized that TRPV2 mediates hypoxic pulmonary vasoconstriction and subsequent vascular remodeling, and tested this using vascular smooth muscle–specific TRPV2-deficient (smTRPV2–/–)mice. smTRPV2–/– mice were generated and compared to…
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AT1a receptors in the subfornical organ increase splenic nerve activity and blood pressure in response to chronic Angiotensin IIM. Perrotta, L. Carnevale, F. Pallante et al. · 2026 · European Heart Journal · Not summarized yet
This study examines brain AT1a receptors regulating splenic sympathetic activity and blood pressure, while the paper traces a neural reflex affecting lung vasculature.
Abstract
Circumventricular organs (CVOs) are important control centers of blood pressure (BP) homeostasis, able to respond to circulating Angiotensin II (AngII) and consequently modulating the activity of peripheral autonomic nervous system. The aim of this study was to investigate whether AngII Type 1a Receptors (AT1aR) in CVOs neurons are directly involved in modulating the splenic sympathetic nerve activity (SSNA) and BP during chronic AngII. First, by injecting fluorescent AngII into femoral vein of C57Bl/6J mice, we observed positivity in the CVOs, specifically in the subfornical organ (SFO) and brainstem, demonstrating that AngII crosses the blood-brain barrier. To investigate whether circulati…
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Updated on 2 November 2026.