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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 Ca 2+ concentration [(Ca 2+ ) 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.

•Impaired functional hyperemia (FH) in aging contributes to vascular dementia. We validate functional ultrasound (fUS) as a novel approach for preclinical assessment of FH in aging.•We demonstrate that fUS can also be used to detect age-related changes in cerebrovascular density through ultrasound localization microscopy, enabling longitudinal tracking of vascular changes with age.•fUS offers greater imaging depth and resolution than other preclinical imaging modalities for FH, enabling detection of changes in smaller vessels and longitudinal studies. Backgrounds and Objectives: Aging is associated with impaired cerebrovascular function, including reduced functional hyperemia (FH), which contributes to cognitive decline and dementia. Unraveling the mechanisms responsible for FH decline during aging is crucial for developing interventions to promote healthy brain aging and mitigate cognitive impairment. Currently, laser speckle contrast imaging (LSCI) serves as the standard method for assessing FH in mouse models of cognitive dysfunction and aging. However, as a terminal procedure, long-term monitoring of changes in FH using LSCI is not possible. Functional ultrasound imaging (fUS) has improved spatial and temporal resolution compared to LSCI and is a promising alternative, but surgical manipulation of the mouse model is necessary to assess FH using fUS. Research Design and Methods: Here, we validated fUS as a novel method for assessing FH and vascular density in mice using a chronological aging model and compared different surgical paradigms. Young and aged mice underwent consecutive imaging with fUS and LSCI following surgical placement of a cranial window. Mice were imaged either acutely or 14 days post window placement. Results: Our findings revealed a robust correlation between the FH measurements obtained from fUS and LSCI in mice allowed to recover for 14 days post window-implantation, underscoring the reliability of fUS as a measurement tool. Similarly, the ability of fUS ultrasound localization microscopy (ULM) to detect age-related vascular rarefaction was improved by the 14-day recovery time after window implantation. Discussion and Implications: This study not only highlights the potential of fUS in FH assessment but also suggests the importance of recovery time post-surgery for optimal cerebrovascular imaging results.

Therapeutic angiogenesis represents an emerging strategy to treat ischemic diseases by stimulating blood vessel growth to rescue local blood perfusion. Therefore, injured microvasculature may be repaired by stimulating resident endothelial cells or circulating endothelial colony forming cells (ECFCs) or by autologous cell-based therapy. Endothelial Ca2+ signals represent a crucial player in angiogenesis and vasculogenesis; indeed, several angiogenic stimuli induce neovessel formation through an increase in intracellular Ca2+ concentration. Several members of the Transient Receptor Potential (TRP) channel superfamily are expressed and mediate Ca2+-dependent functions in vascular endothelial cells and in ECFCs, the only known truly endothelial precursor. TRP Vanilloid 1 (TRPV1), a polymodal cation channel, is emerging as an important player in endothelial cell migration, proliferation, and tubulogenesis, through the integration of several chemical stimuli. Herein, we first summarize TRPV1 structure and gating mechanisms. Next, we illustrate the physiological roles of TRPV1 in vascular endothelium, focusing our attention on how endothelial TRPV1 promotes angiogenesis. In particular, we describe a recent strategy to stimulate TRPV1-mediated pro-angiogenic activity in ECFCs, in the presence of a photosensitive conjugated polymer. Taken together, these observations suggest that TRPV1 represents a useful target in the treatment of ischemic diseases.

Age-related cerebromicrovascular changes, including blood-brain barrier (BBB) disruption and microvascular rarefaction, play a significant role in the development of vascular cognitive impairment (VCI) and neurodegenerative diseases. Utilizing the unique model of heterochronic parabiosis, which involves surgically joining young and old animals, we investigated the influence of systemic factors on these vascular changes. Our study employed heterochronic parabiosis to explore the effects of young and aged systemic environments on cerebromicrovascular aging in mice. We evaluated microvascular density and BBB integrity in parabiotic pairs equipped with chronic cranial windows, using intravital two-photon imaging techniques. Our results indicate that short-term exposure to young systemic factors leads to both functional and structural rejuvenation of cerebral microcirculation. Notably, we observed a marked decrease in capillary density and an increase in BBB permeability to fluorescent tracers in the cortices of aged mice undergoing isochronic parabiosis (20-month-old C57BL/6 mice [A-(A)]; 6 weeks of parabiosis), compared to young isochronic parabionts (6-month-old, [Y-(Y)]). However, aged heterochronic parabionts (A-(Y)) exposed to young blood exhibited a significant increase in cortical capillary density and restoration of BBB integrity. In contrast, young mice exposed to old blood from aged parabionts (Y-(A)) rapidly developed cerebromicrovascular aging traits, evidenced by reduced capillary density and increased BBB permeability. These findings underscore the profound impact of systemic factors in regulating cerebromicrovascular aging. The rejuvenation observed in the endothelium, following exposure to young blood, suggests the existence of anti-geronic elements that counteract microvascular aging. Conversely, pro-geronic factors in aged blood appear to accelerate cerebromicrovascular aging. Further research is needed to assess whether the rejuvenating effects of young blood factors could extend to other age-related cerebromicrovascular pathologies, such as microvascular amyloid deposition and increased microvascular fragility.

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.

Aging impairs cerebrovascular structure and function, contributing to cognitive decline and dementia. Here, a novel, high‐resolution, intravital imaging platform is presented that combines functional ultrasound (fUS) and ultrasound localization microscopy (ULM) through a chronically implanted, polymethylpentene (TPX) cranial window, a transparent implant that enables ultrasound imaging through the skull. This approach enables intravital, longitudinal, minimally invasive assessment of cerebrovascular structure and function across cortical and deep brain regions. Leveraging this platform, a new method is developed to estimate resting cerebral blood flow (CBF) by integrating microbubble (MB) velocity data from fUS with microvascular geometry derived from ULM. Notably, a significant age‐related decline in the cortical arteriole‐to‐venule ratio (AVR) is discovered, introducing a novel biomarker of structural cerebrovascular remodeling. It is also validated that fUS can reliably assess neurovascular coupling (NVC) responses in aged mice. This study establishes a powerful, non‐invasive, and repeatable investigative tool for future preclinical studies aimed at evaluating the efficacy of therapeutic interventions targeting vascular contributions to cognitive impairment and neurodegeneration. A high‐resolution intravital imaging platform combining functional ultrasound and localization microscopy enables longitudinal, minimally invasive assessment of cerebrovascular function in aging studies. The present investigation reveals aging‐related reductions in neurovascular coupling, arteriole‐to‐venule ratio and vascular density, introducing a powerful approach to investigate cerebrovascular remodeling and its contribution to cognitive decline and neurodegeneration.

It has long been known that the conditionally essential polyunsaturated arachidonic acid (AA) regulates cerebral blood flow (CBF) through its metabolites prostaglandin E2 and epoxyeicosatrienoic acid, which act on vascular smooth muscle cells and pericytes to vasorelax cerebral microvessels. However, AA may also elicit endothelial nitric oxide (NO) release through an increase in intracellular Ca2+ concentration ([Ca2+]i). Herein, we adopted Ca2+ and NO imaging, combined with immunoblotting, to assess whether AA induces intracellular Ca2+ signals and NO release in the human brain microvascular endothelial cell line hCMEC/D3. AA caused a dose-dependent increase in [Ca2+]i that was mimicked by the not-metabolizable analogue, eicosatetraynoic acid. The Ca2+ response to AA was patterned by endoplasmic reticulum Ca2+ release through type 3 inositol-1,4,5-trisphosphate receptors, lysosomal Ca2+ mobilization through two-pore channels 1 and 2 (TPC1-2), and extracellular Ca2+ influx through transient receptor potential vanilloid 4 (TRPV4). In addition, AA-evoked Ca2+ signals resulted in robust NO release, but this signal was considerably delayed as compared to the accompanying Ca2+ wave and was essentially mediated by TPC1-2 and TRPV4. Overall, these data provide the first evidence that AA elicits Ca2+-dependent NO release from a human cerebrovascular endothelial cell line, but they seemingly rule out the possibility that this NO signal could acutely modulate neurovascular coupling.