The role of endothelial TRP channels in age-related vascular cognitive impairment and dementia

Transient receptor potential (TRP) proteins are part of a superfamily of polymodal cation channels that can be activated by mechanical, physical, and chemical stimuli. In the vascular endothelium, TRP channels regulate two fundamental parameters: the membrane potential and the intracellular Ca2+ concentration [(Ca2+)i]. TRP channels are widely expressed in the cerebrovascular endothelium, and are emerging as important mediators of several brain microvascular functions (e.g., neurovascular coupling, endothelial function, and blood–brain barrier permeability), which become impaired with aging. Aging is the most significant risk factor for vascular cognitive impairment (VCI), and the number of individuals affected by VCI is expected to exponentially increase in the coming decades. Yet, there are currently no preventative or therapeutic treatments available against the development and progression of VCI. In this review, we discuss the involvement of endothelial TRP channels in diverse physiological processes in the brain as well as in the pathogenesis of age-related VCI to explore future potential neuroprotective strategies

Nicotinic Acid Adenine Dinucleotide Phosphate Induces Intracellular Ca2+ Signalling and Stimulates Proliferation in Human Cardiac Mesenchymal Stromal Cells

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a newly discovered second messenger that gates two pore channels 1 (TPC1) and 2 (TPC2) to elicit endo-lysosomal (EL) Ca2+ release. NAADP-induced lysosomal Ca2+ release may be amplified by the endoplasmic reticulum (ER) through the Ca2+-induced Ca2+ release (CICR) mechanism. NAADP-induced intracellular Ca2+ signals were shown to modulate a growing number of functions in the cardiovascular system, but their occurrence and role in cardiac mesenchymal stromal cells (C-MSCs) is still unknown. Herein, we found that exogenous delivery of NAADP-AM induced a robust Ca2+ signal that was abolished by disrupting the lysosomal Ca2+ store with Gly-Phe β-naphthylamide, nigericin, and bafilomycin A1, and blocking TPC1 and TPC2, that are both expressed at protein level in C-MSCs. Furthermore, NAADP-induced EL Ca2+ release resulted in the Ca2+-dependent recruitment of ER-embedded InsP3Rs and SOCE activation. Transmission electron microscopy revealed clearly visible membrane contact sites between lysosome and ER membranes, which are predicted to provide the sub-cellular framework for lysosomal Ca2+ to recruit ER-embedded InsP3Rs through CICR. NAADP-induced EL Ca2+ mobilization via EL TPC was found to trigger the intracellular Ca2+ signals whereby Fetal Bovine Serum (FBS) induces C-MSC proliferation. Furthermore, NAADP-evoked Ca2+ release was required to mediate FBS-induced extracellular signal-regulated kinase (ERK), but not Akt, phosphorylation in C-MSCs. These finding support the notion that NAADP-induced TPC activation could be targeted to boost proliferation in C-MSCs and pave the way for future studies assessing whether aberrant NAADP signaling in C-MSCs could be involved in cardiac disorders

Ca2+ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide

BACKGROUND: Cardiac mesenchymal stromal cells (C-MSC) were recently shown to differentiate into adipocytes and myofibroblasts to promote the aberrant remodeling of cardiac tissue that characterizes arrhythmogenic cardiomyopathy (ACM). A calcium (Ca(2+)) signaling dysfunction, mainly demonstrated in mouse models, is recognized as a mechanism impacting arrhythmic risk in ACM cardiomyocytes. Whether similar mechanisms influence ACM C-MSC fate is still unknown. Thus, we aim to ascertain whether intracellular Ca(2+) oscillations and the Ca(2+) toolkit are altered in human C-MSC obtained from ACM patients, and to assess their link with C-MSC-specific ACM phenotypes. METHODS AND RESULTS: ACM C-MSC show enhanced spontaneous Ca(2+) oscillations and concomitant increased Ca(2+)/Calmodulin dependent kinase II (CaMKII) activation compared to control cells. This is manly linked to a constitutive activation of Store-Operated Ca(2+) Entry (SOCE), which leads to enhanced Ca(2+) release from the endoplasmic reticulum through inositol-1,4,5-trisphosphate receptors. By targeting the Ca(2+) handling machinery or CaMKII activity, we demonstrated a causative link between Ca(2+) oscillations and fibro-adipogenic differentiation of ACM C-MSC. Genetic silencing of the desmosomal gene PKP2 mimics the remodelling of the Ca(2+) signalling machinery occurring in ACM C-MSC. The anti-arrhythmic drug flecainide inhibits intracellular Ca(2+) oscillations and fibro-adipogenic differentiation by selectively targeting SOCE. CONCLUSIONS: Altogether, our results extend the knowledge of Ca(2+) dysregulation in ACM to the stromal compartment, as an etiologic mechanism of C-MSC-related ACM phenotypes. A new mode of action of flecainide on a novel mechanistic target is unveiled against the fibro-adipose accumulation in ACM. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-022-03742-8

2018 Atmospheric Motion Vector (AMV): intercomparison study

Atmospheric Motion Vectors (AMVs) calculated by six different institutions (Brazil Center for Weather Prediction and Climate Studies/CPTEC/INPE, European Organization for the Exploitation of Meteorological Satellites/EUMETSAT, Japan Meteorological Agency/JMA, Korea Meteorological Administration/KMA, Unites States National Oceanic and Atmospheric Administration/NOAA, and the Satellite Application Facility on Support to Nowcasting and Very short range forecasting/NWCSAF) with JMA’s Himawari-8 satellite data and other common input data are here compared. The comparison is based on two different AMV input datasets, calculated with two different image triplets for 21 July 2016, and the use of a prescribed and a specific configuration. The main results of the study are summarized as follows: (1) the differences in the AMV datasets depend very much on the ‘AMV height assignment’ used and much less on the use of a prescribed or specific configuration; (2) the use of the ‘Common Quality Indicator (CQI)’ has a quantified skill in filtering collocated AMVs for an improved statistical agreement between centers; (3) Among the six AMV operational algorithms verified by this AMV Intercomparison, JMA AMV algorithm has the best overall performance considering all validation metrics, mainly due to its new height assignment method: ‘Optimal estimation method considering the observed infrared radiances, the vertical profile of the Numerical Weather Prediction wind, and the estimated brightness temperature using a radiative transfer model’.The “Space Science and Engineering Center” (SSEC) of the “University ofWisconsin-Madison” (UW) was funded to do this research by the “European Organization for the Exploitation of Meteorological Satellites (EUMETSAT)”, through the “Satellite Application Facility on Support to Nowcasting and Very short range forecasting (NWCSAF)” “Visiting Scientist Activity (VSA)” program

The Profanation of Revelation: On Language and Immanence in the Work of Giorgio Agamben

This essay seeks to articulate the many implications which Giorgio Agamben’s work holds for theology. It aims therefore to examine his (re)conceptualizations of language, in light of particular historical glosses on the ‘name of God’ and the nature of the ‘mystical’, as well as to highlight the political task of profanation, one of his most central concepts, in relation to the logos said to embody humanity’s ‘religious’ quest to find its Voice. As such, we see how he challenges those standard (ontotheological) notions of transcendence which have been consistently aligned with various historical forms of sovereignty. In addition, I intend to present his redefinition of revelation as solely the unveiling of the ‘name of God’ as the fact of our linguistic being, a movement from the transcendent divine realm to the merely human world before us. By proceeding in this manner, this essay tries to close in on one of the largest theological implications contained within Agamben’s work: the establishment of an ontology that could only be described as a form of ‘absolute’ immanence, an espousal of some form of pantheism (or perhaps panentheism) yet to be more fully pronounced within his writings

Targeting endothelial ion signalling to rescue cerebral blood flow in cerebral disorders

The mechanism whereby an increase in neuronal activity (NA) leads to a local elevation in cerebral blood flow to supply the active neurons with oxygen and nutrients and remove the catabolic waste has been termed neurovascular coupling (NVC). Although it has long been thought that the vasoactive mediators involved in NVC are generated by neurons and astrocytes, recent evidence unveiled the crucial role of cerebrovascular endothelial cells in NVC. Brain capillary endothelial cells express a complement of ion channels, including inward-rectifier K+ (Kir2.1) channels, Transient Receptor Potential Ankyrin 1 channels and N-methyl-d-aspartate receptors that enable them to sense NA and thereby initiate the retrograde transmission of both electrical (via endothelium-dependent hyperpolarization) and chemical (via intercellular Ca2+ waves also sustained by TRP Vanilloid 4 channels and inositol-1,4,5-trisphosphate receptors) signals that induce vasodilation in upstream pial arteries and parenchymal arteries. Notably, a defect in the endothelial ion channel machinery (particularly, Kir2.1 channels) contributes to vascular cognitive impairment and dementia that features many cerebral disorders, including Alzheimer's disease, cerebral small vessel diseases, and traumatic brain injury. Targeting endothelial ion channels through appropriate pharmacological approaches might represent a hitherto unappreciated strategy to rescue CBF and prevent cognitive impairment and dementia in patients affected by cerebral disorders