Dataset Information

Low wnt/β-catenin signaling determines leaky vessels in the subfornical organ and affects water homeostasis in mice.

ABSTRACT: The circumventricular organs (CVOs) in the central nervous system (CNS) lack a vascular blood-brain barrier (BBB), creating communication sites for sensory or secretory neurons, involved in body homeostasis. Wnt/β-catenin signaling is essential for BBB development and maintenance in endothelial cells (ECs) in most CNS vessels. Here we show that in mouse development, as well as in adult mouse and zebrafish, CVO ECs rendered Wnt-reporter negative, suggesting low level pathway activity. Characterization of the subfornical organ (SFO) vasculature revealed heterogenous claudin-5 (Cldn5) and Plvap/Meca32 expression indicative for tight and leaky vessels, respectively. Dominant, EC-specific β-catenin transcription in mice, converted phenotypically leaky into BBB-like vessels, by augmenting Cldn5+vessels, stabilizing junctions and by reducing Plvap/Meca32+ and fenestrated vessels, resulting in decreased tracer permeability. Endothelial tightening augmented neuronal activity in the SFO of water restricted mice. Hence, regulating the SFO vessel barrier may influence neuronal function in the context of water homeostasis.

SUBMITTER: Benz F

PROVIDER: S-EPMC6481993 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Low wnt/β-catenin signaling determines leaky vessels in the subfornical organ and affects water homeostasis in mice.

Benz Fabienne F Wichitnaowarat Viraya V Lehmann Martin M Germano Raoul Fv RF Mihova Diana D Macas Jadranka J Adams Ralf H RH Taketo M Mark MM Plate Karl-Heinz KH Guérit Sylvaine S Vanhollebeke Benoit B Liebner Stefan S

eLife 20190401

The circumventricular organs (CVOs) in the central nervous system (CNS) lack a vascular blood-brain barrier (BBB), creating communication sites for sensory or secretory neurons, involved in body homeostasis. Wnt/β-catenin signaling is essential for BBB development and maintenance in endothelial cells (ECs) in most CNS vessels. Here we show that in mouse development, as well as in adult mouse and zebrafish, CVO ECs rendered Wnt-reporter negative, suggesting low level pathway activity. Characteriz ...[more]

PMID: 30932814

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Project description:Our previous work indicated that the subfornical organ (SFO) is an important brain sensor of blood-borne proinflammatory cytokines, mediating their central effects on autonomic and cardiovascular function. However, the mechanisms by which SFO mediates the central effects of circulating proinflammatory cytokines remain unclear. We hypothesized that proinflammatory cytokines act within the SFO to upregulate the expression of excitatory and inflammatory mediators that drive sympathetic nerve activity. In urethane-anesthetized Sprague-Dawley rats, direct microinjection of tumor necrosis factor (TNF)-α (25 ng) or interleukin (IL)-1β (25 ng) into SFO increased mean blood pressure, heart rate, and renal sympathetic nerve activity within 15 to 20 minutes, mimicking the response to systemically administered proinflammatory cytokines. Pretreatment of SFO with microinjections of the angiotensin II type-1 receptor blocker losartan (1 μg), angiotensin-converting enzyme inhibitor captopril (1 μg) or cyclooxygenase-2 inhibitor NS-398 (2 μg) attenuated those responses. Four hours after the SFO microinjection of TNF-α (25 ng) or IL-1β (25 ng), mRNA for angiotensin-converting enzyme, angiotensin II type-1 receptor, TNF-α and the p55 TNF-α receptor, IL-1β and the IL-1R receptor, and cyclooxygenase-2 had increased in SFO, and mRNA for angiotensin-converting enzyme, angiotensin II type-1 receptor, and cyclooxygenase-2 had increased downstream in the hypothalamic paraventricular nucleus. Confocal immunofluorescent images revealed that immunoreactivity for the p55 TNF-α receptor and the IL-1 receptor accessory protein, a subunit of the IL-1 receptor, colocalized with angiotensin-converting enzyme, angiotensin II type-1 receptor-like, cyclooxygenase-2, and prostaglandin E2 EP3 receptor immunoreactivity in SFO neurons. These data suggest that proinflammatory cytokines act within the SFO to upregulate the expression of inflammatory and excitatory mediators that drive sympathetic excitation.

Dataset Information

Low wnt/β-catenin signaling determines leaky vessels in the subfornical organ and affects water homeostasis in mice.

Publications

Low wnt/β-catenin signaling determines leaky vessels in the subfornical organ and affects water homeostasis in mice.

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