Neuronally differentiated endothelial cell subtype regulates organ blood flow and immune balance

Gyarmati, G.; Rust, R.; Calderon, A. B.; Izuhara, A.; Trogen, G.; Deepak, S.; Chen, Y.; Ruffins, S. W.; Junge, J. A.; Zlokovic, B. V.; Fraser, S. E.; Peti-Peterdi, J.

doi:10.1101/2024.09.30.615824

bioRxiv · 10.1101/2024.09.30.615824

Neuronally differentiated endothelial cell subtype regulates organ blood flow and immune balance

Gyarmati, G.·Rust, R.·Calderon, A. B.·Izuhara, A.·Trogen, G.·Deepak, S.·Chen, Y.·Ruffins, S. W.·Junge, J. A.·Zlokovic, B. V.·Fraser, S. E.·Peti-Peterdi, J.

View original source ↗Export metadata ↓

Abstract

Vascular endothelial cells (ECs) perform key pleiotropic functions to maintain body homeostasis via the regulation of organ blood flow, vascular permeability, tissue growth and inflammation, and angiogenesis. Recent transcriptomic studies uncovered many EC subtypes across organs; however their specific functions are incompletely understood. Here we identified and characterized a novel, minority subtype of scattered ECs with a well-defined arteriovenous zonal localization exclusively in small resistance (strain) arterioles, and with the highest density in the brain>retina>kidney. Due to their expression of both endothelial and neuron-like functional and gene transcriptomic signatures, they were termed neuro-endothelial cells (NECs). High resolution single-cell transcriptome analysis of mouse brain and kidney ECs identified neuronal nitric oxide synthase (Nos1) and cytokine-like 1 (Cytl1) as top NEC biomarkers. Intravital multiphoton imaging of optogenetic mouse models with NEC gain/loss-of-function revealed NEC and Nos1-dependent vasodilation/vasoconstriction of intact brain and kidney arterioles and elevation/reduction in blood flow. Silencing NEC Nos1 and Cytl1 gene expression in vivo caused marked segmental arteriolar vasoconstrictions, reductions in vascular density and organ blood flow, increased vascular permeability and immune cell homing. Cytl1 administration triggered vasodilation and increased blood flow acutely, and increased capillary density and clonal EC remodeling chronically. NECs play major vasodilatory, angiogenic and anti-inflammatory functions that may be therapeutically targeted for vascular and inflammatory diseases.

Explore related subjects

physiology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Gyarmati, G., Rust, R., Calderon, A. B., Izuhara, A., Trogen, G., Deepak, S., Chen, Y., Ruffins, S. W., Junge, J. A., Zlokovic, B. V., Fraser, S. E., Peti-Peterdi, J.. 2024-10-02. Neuronally differentiated endothelial cell subtype regulates organ blood flow and immune balance. https://doi.org/10.1101/2024.09.30.615824

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Cholinergic impairment in the dorsal motor nucleus of the vagus during experimental Alzheimer's disease

Cholinergic neurons in the dorsal motor nucleus of the vagus (DMN) in the brainstem are a key source of efferent vagus nerve fibers that regulate vital functions, including heart rate and inflammation. Whether the integrity of DMN cholinergic neurons is affected during Alzheimer's disease (AD) remains unknown. Here, in female and male mice with experimental AD (5xFAD), which exhibit age-dependent memory impairment, basal forebrain cholinergic neurodegeneration, and microglial alterations, we observe a reduction in cholinergic neuron density in the DMN at 6 and 10 months of age. Furthermore, while an important physiological function of DMN cholinergic signaling, such as suppression of heart rate, is preserved in control mice upon electrical DMN stimulation, the extent of suppression diminishes with age in both female and male 5xFAD mice. In addition, while electrical DMN stimulation lowers pro-inflammatory cytokine levels in control mice subjected to endotoxemia, this anti-inflammatory effect is diminished with age in 5xFAD mice, with females showing earlier dysfunction at 6 months. These results reveal previously unrecognized age-dependent cholinergic deficits in the DMN and disrupted brain - to - periphery vagus nerve circuits in experimental AD. These findings advance our understanding of AD mechanisms and are of interest for the development of conceptually novel therapies.

physiology↗

bioRxiv2026

Ketogenic diet is protective during endotoxin-induced lung injury through the elevation of BHB

Acute respiratory distress syndrome (ARDS) is marked by severe pulmonary edema and concomitant hypoxia, affecting hundreds of thousands of people a year, especially those in critical care conditions or suffering from septic shock. Previous studies have implicated that the ketogenic diet, a high-fat and low-carbohydrate diet, modulates inflammatory responses. However, the impact of the ketogenic diet on septic ARDS outcomes is unknown. Here, we demonstrated that mice on a ketogenic diet showed strikingly reduced lung injury and inflammation compared to those on a control diet during a murine model of endotoxin-induced lung injury, induced by intratracheal lipopolysaccharide (LPS) injection. Immune mass cytometry studies on lung tissue indicated that the ketogenic diet reduces immune cell infiltration. Treating mice with beta-hydroxybutyrate (BHB), the primary metabolite of ketogenesis, after the onset of ARDS reduced pulmonary edema and lung inflammation, as well as NF-kB activity, suggesting strong therapeutic potential. By multiplex analysis in bronchial alveolar lavage fluid, we observed that the ketogenic diet or BHB administration attenuates the chemotaxis and activation of immune cells. Altogether, our findings reveal that the ketogenic diet provides lung protection during endotoxin-induced lung injury through BHB.

physiology↗

bioRxiv2026

Efficacy of postmenopausal estrogen replacement in SIV-infected female macaques on antiretroviral therapy.

The success of modern antiretroviral therapy (ART) has increased the life expectancy of people living with HIV to levels approaching that of uninfected individuals. For women living with HIV (WLWH), this means that more will survive to undergo menopause and experience the consequences of decreased ovarian hormone levels, particularly estrogen (E2). The recent change in federal guidance for use of postmenopausal hormone therapy is increasing demand for both E2-alone and E2+progestogen formulations to control adverse symptoms of menopause. The consequences and efficacy of hormone therapy in WLWH are thus an important issue for WLWH and their healthcare providers. The role of E2 replacement in postmenopausal WLWH is a significant issue because of its potential effects on control the viral reservoir and its demonstrated beneficial metabolic effects in uninfected postmenopausal women. To address these questions, we employed a novel nonhuman primate model of postmenopausal WLWH undergoing E2 replacement. Reproductively competent female rhesus macaques were infected with simian immunodeficiency virus (SIV) and then subjected to a daily ART regimen. After complete suppression of plasma viremia, all animals were ovariectomized (OVX) and then implanted with Silastic capsules containing either cholesterol vehicle or sufficient E2 to restore pre-OVX plasma levels. Plasma and cell-associated viral dynamics, immune responses, body composition, systemic and tissue-specific metabolic parameters, cytokine profiles, and parameters of bone health were followed longitudinally from baseline through 34 weeks of E2 deficiency or replacement. We found that E2 status did not significantly affect plasma or tissue viral dynamics or overall metabolic homeostasis. However, E2 replacement exerted beneficial effects on several aspects of bone health in spite of a chronic inflammatory state that persisted following effective ART suppression of the SIV reservoir. Our findings suggest that hormone therapy, specifically E2 replacement, offers benefit to WLWH, particularly with respect to bone loss.

physiology↗