Review of the Role of TRAF7 in Brain Endothelial Integrity and Cerebrovascular Aging.

Tumor necrosis factor (TNF) receptor-associated factor 7 (TRAF7) is a signal transducer in the TNF receptor superfamily. TRAF7 is unique among its superfamily in that it does not contain a TRAF-C domain but does contain WD-40 domains. TRAF7 interacts with mitogen-activated protein kinases (MAPK), which are known regulators of inflammation and shear stress response.

Functional ultrasound as a quantitative approach for measuring functional hyperemia in aging models.

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.

Effects of NAD supplementation with oral nicotinamide riboside on vascular health and cognitive function in older adults with peripheral artery disease: Results from a pilot 4-week open-label clinical trial.

Peripheral artery disease (PAD) significantly contributes to increased morbidity and mortality among older adults. Characterized by generalized endothelial dysfunction, PAD is associated with a heightened risk for cerebral small vessel disease and vascular cognitive impairment. Together, these conditions exemplify the phenomenon of accelerated systemic vascular aging, highlighting the interconnections between vascular health and cognitive functions in the elderly.

Endothelial IGF- 1R deficiency disrupts microvascular homeostasis, impairing skeletal muscle perfusion and endurance: implications for age-related sarcopenia.

Aging is associated with a progressive decline in circulating insulin-like growth factor- 1 (IGF- 1) levels in humans, which has been implicated in the pathogenesis of sarcopenia. IGF- 1 is an anabolic hormone that plays a dual role in maintaining skeletal muscle health, acting both directly on muscle fibers to promote growth and indirectly by supporting the vascular network that sustains muscle perfusion. However, the microvascular consequences of IGF- 1 deficiency in aging muscle remain poorly understood.

Senescent Endothelial Cells in Cerebral Microcirculation Are Key Drivers of Age-Related Blood-Brain Barrier Disruption, Microvascular Rarefaction, and Neurovascular Coupling Impairment in Mice.

With advancing age, neurovascular dysfunction manifests as impaired neurovascular coupling (NVC), microvascular rarefaction, and blood-brain barrier (BBB) disruption, contributing to vascular cognitive impairment (VCI). Our previous research established a causal link between vascular senescence induced cerebromicrovascular dysfunction and cognitive decline in accelerated aging models. The present study examines whether chronological aging promotes endothelial senescence, adversely affecting neurovascular health, and whether senolytic therapies can enhance neurovascular function and cognitive performance in aged mice.

Functional ultrasound imaging reveals microvascular rarefaction, decreased cerebral blood flow, and impaired neurovascular coupling in a mouse model of paclitaxel-induced chemobrain.

Chemotherapy-induced cognitive impairment (CICI), often referred to as "chemobrain," significantly affects the quality of life in cancer survivors. Although traditionally attributed to neuronal toxicity, emerging evidence suggests a key role of cerebrovascular dysfunction in its pathogenesis. We hypothesized that paclitaxel (PTX, Taxol) treatment induces long-term cerebrovascular dysfunction, including microvascular rarefaction, impaired neurovascular coupling (NVC), and altered cerebral blood flow (CBF), which contribute to CICI.

Endothelial Colony-Forming Cells (ECFCs) in cerebrovascular aging: Focus on the pathogenesis of Vascular Cognitive Impairment and Dementia (VCID), and treatment prospects.

Endothelial colony-forming cells (ECFCs), a unique endothelial progenitor subset, are essential for vascular integrity and repair, providing significant regenerative potential. Recent studies highlight their role in cerebrovascular aging, particularly in the pathogenesis of vascular cognitive impairment and dementia (VCID). Aging disrupts ECFC functionality through mechanisms such as oxidative stress, chronic inflammation, and cellular senescence, leading to compromised vascular repair and reduced neurovascular resilience.

An automated planar patch-clamp approach to measure the membrane potential and resting membrane currents in a human cerebrovascular endothelial cell line.

Background: The conventional "whole-cell patch-clamp" recording technique is widely used to measure the resting membrane potential (V) and to dissect the underlying membrane ionic conductances in isolated vascular endothelial cells.

New Method: Herein, we assessed whether the automated patch-clamp (APC) technology, which replaces the traditional patch-pipette with a planar substrate to permit researchers lacking formal training in electrophysiology to generate large amounts of data in a relatively short time, can be used to characterize the bioelectrical activity of vascular endothelial cells. We assessed whether the Port-a-Patch planar patch-clamp system, which is regarded as the smallest electrophysiological rig available on the market, can be used to measure the V and resting membrane currents in the human cerebrovascular endothelial cell line, hCMEC/D3.

The effects of time restricted feeding on age-related changes in the mouse retina.

Dietary modifications such as caloric restriction (CR) and intermittent fasting (IF) have gained popularity due to their proven health benefits in aged populations. In time restricted feeding (TRF), a form of intermittent fasting, the amount of time for food intake is regulated without restricting the caloric intake. TRF is beneficial for the central nervous system to support brain health in the context of aging.

Longitudinal detection of gait alterations associated with hypertension-induced cerebral microhemorrhages in mice: predictive role of stride length and stride time asymmetry and increased gait entropy.

Cerebral microhemorrhages (CMHs) are of paramount importance as they not only signify underlying vascular pathology but also have profound implications for cognitive function and neurological health, serving as a critical indicator for the early detection and management of vascular cognitive impairment (VCI). This study aimed to investigate the effects of hypertension-induced CMHs on gait dynamics in a mouse model, focusing on the utility of advanced gait metrics as sensitive indicators of subclinical neurological alterations associated with CMHs. To induce CMHs, we employed a hypertensive mouse model, using a combination of Angiotensin II and L-NAME to elevate blood pressure, further supplemented with phenylephrine to mimic transient blood pressure fluctuations.

Young blood-mediated cerebromicrovascular rejuvenation through heterochronic parabiosis: enhancing blood-brain barrier integrity and capillarization in the aged mouse brain.

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.

Rejuvenation of cerebromicrovascular function in aged mice through heterochronic parabiosis: insights into neurovascular coupling and the impact of young blood factors.

Age-related impairment of neurovascular coupling (NVC; "functional hyperemia") is a critical factor in the development of vascular cognitive impairment (VCI). Recent geroscience research indicates that cell-autonomous mechanisms alone cannot explain all aspects of neurovascular aging. Circulating factors derived from other organs, including pro-geronic factors (increased with age and detrimental to vascular homeostasis) and anti-geronic factors (preventing cellular aging phenotypes and declining with age), are thought to orchestrate cellular aging processes.

Preventing spontaneous cerebral microhemorrhages in aging mice: a novel approach targeting cellular senescence with ABT263/navitoclax.

Emerging evidence from both clinical and preclinical studies underscores the role of aging in potentiating the detrimental effects of hypertension on cerebral microhemorrhages (CMHs, or cerebral microbleeds). CMHs progressively impair neuronal function and contribute to the development of vascular cognitive impairment and dementia. There is growing evidence showing accumulation of senescent cells within the cerebral microvasculature during aging, which detrimentally affects cerebromicrovascular function and overall brain health.

The Role of Methionine-Rich Diet in Unhealthy Cerebrovascular and Brain Aging: Mechanisms and Implications for Cognitive Impairment.

As aging societies in the western world face a growing prevalence of vascular cognitive impairment and Alzheimer's disease (AD), understanding their underlying causes and associated risk factors becomes increasingly critical. A salient concern in the western dietary context is the high consumption of methionine-rich foods such as red meat. The present review delves into the impact of this methionine-heavy diet and the resultant hyperhomocysteinemia on accelerated cerebrovascular and brain aging, emphasizing their potential roles in cognitive impairment.

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 Ca concentration [(Ca)]. TRP channels are widely expressed in the cerebrovascular endothelium, and are emerging as important mediators of several brain microvascular functions (e.

Hydrogen Sulfide (HS): As a Potent Modulator and Therapeutic Prodrug in Cancer.

Hydrogen sulfide (HS) is an endogenous gaseous molecule present in all living organisms that has been traditionally studied for its toxicity. Interestingly, increased understanding of HS effects in organ physiology has recently shown its relevance as a signalling molecule, with potentially important implications in variety of clinical disorders, including cancer. HS is primarily produced in mammalian cells under various enzymatic pathways are target of intense research biological mechanisms, and therapeutic effects of HS.

GABA and GABA Receptors Mediate GABA-Induced Intracellular Ca Signals in Human Brain Microvascular Endothelial Cells.

Numerous studies recently showed that the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), can stimulate cerebral angiogenesis and promote neurovascular coupling by activating the ionotropic GABA receptors on cerebrovascular endothelial cells, whereas the endothelial role of the metabotropic GABA receptors is still unknown. Preliminary evidence showed that GABA receptor stimulation can induce an increase in endothelial Ca levels, but the underlying signaling pathway remains to be fully unraveled. In the present investigation, we found that GABA evoked a biphasic elevation in [Ca] that was initiated by inositol-1,4,5-trisphosphate- and nicotinic acid adenine dinucleotide phosphate-dependent Ca release from neutral and acidic Ca stores, respectively, and sustained by store-operated Ca entry.

Ca 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) 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.

Platelet-Derived Extracellular Vesicles Stimulate Migration through Partial Remodelling of the Ca Handling Machinery in MDA-MB-231 Breast Cancer Cells.

Background: Platelets can support cancer progression via the release of microparticles and microvesicles that enhance the migratory behaviour of recipient cancer cells. We recently showed that platelet-derived extracellular vesicles (PEVs) stimulate migration and invasiveness in highly metastatic MDA-MB-231 cells by stimulating the phosphorylation of p38 MAPK and the myosin light chain 2 (MLC2). Herein, we assessed whether the pro-migratory effect of PEVs involves the remodelling of the Ca handling machinery, which drives MDA-MB-231 cell motility.