Elder abuse geriatrics: describing an important new medical specialist.

Elder mistreatment, including elder abuse and neglect, is a difficult diagnosis to make and manage for most providers. To address this, two elder abuse consultation teams were developed for patients in the hospital and emergency department settings. As these teams have developed, the providers involved have obtained specialized training and experience that we believe contributes to a new field of elder abuse geriatrics, a corollary to the well-established field of child abuse pediatrics. Providers working in this field require specialized training and have a specialized scope of practice that includes forensic evaluation, evaluation of cognition and capacity, care coordination and advocacy for victims of abuse, and collaboration with protective services and law enforcement. Here we describe the training, scope of practice, ethical role, and best practices for elder mistreatment medical consultation. We hope this will serve as a starting point for this new and important medical specialty.

ED/hospital program contributions to community multi-disciplinary team meetings: Different models.

Elder mistreatment (EM) is a complex problem, with response and prevention requiring contributions from professionals from many disciplines. Community-based multi-disciplinary teams (MDTs) that conduct meetings to discuss challenging cases and coordinate services are a common strategy to ensure effective collaboration. Though they play an important role in EM identification, intervention, and prevention, hospitals and hospital-based healthcare professionals have been particularly difficult to engage in MDTs. Two hospitals in different communities recently launched Emergency Department (ED)/hospital-based response teams to consult in cases of potential EM, and both participate in MDTs. We explored similarities and differences between the MDTs in these communities including in the role of the ED/hospital-based response team. The comparison demonstrates both core common features as well as large variations. These differences reflect different circumstances in the models on which they were based, on MDT development in these communities, available resources and infrastructure, and the ED/hospital program's role.

Strategies for dissemination of ED/hospital elder mistreatment response team model.

Interdisciplinary Emergency Department/hospital-based teams represent a promising care model to improve identification of and intervention for elder mistreatment. Two institutions, Weill Cornell Medicine/NewYork-Presbyterian Hospital and the University of Colorado Anschutz Medical Campus have launched such programs and are exploring multiple strategies for effective dissemination. These strategies include: (1) program evaluation research, (2) framing as a new model of geriatric care, (3) understanding the existing incentives of health systems, EDs, and hospitals to align with them, (4) connecting to ongoing ED/hospital initiatives, (5) identifying and collaborating with communities with strong elder mistreatment response that want to integrate the ED/hospital, (6) developing and making easily accessible high-quality, comprehensive protocols and training materials, (7) offering technical assistance and support, (8) communications outreach to raise awareness, and (9) using an existing framework to inform implementation in new hospitals and health systems.

Initial steps in addressing the challenges of elder mistreatment evaluation: Protocol for evaluating the Vulnerable Elder Protection Team.

INTRODUCTION: Although many programmes have been developed to address elder mistreatment, high-quality, rigorous evaluations to assess their impact are lacking. This is partly due to challenges in conducting programme evaluation for such a complex phenomenon. We describe here the development of a protocol to mitigate these challenges and rigorously evaluate a first-of-its-kind emergency department/hospital-based elder mistreatment intervention, the Vulnerable Elder Protection Team (VEPT). METHODS AND ANALYSIS: We used a multistep process to develop an evaluation protocol for VEPT: (1) creation of a logic model to describe programme activities and relevant short-term and long-term outcomes, (2) operationalisation of these outcome measures, (3) development of a combined outcome and (4) design of a protocol using telephone follow-up at multiple time points to obtain information about older adults served by VEPT. This protocol, which is informing an ongoing evaluation of VEPT, may help researchers and health system leaders design evaluations for similar elder mistreatment programmes. ETHICS AND DISSEMINATION: This project has been reviewed and approved by the Weill Cornell Medicine Institutional Review Board, protocol #20-02021422. We aim to disseminate our results in peer-reviewed journals at national and international conferences and among interested patient groups and the public.

Allogeneic immunity clears latent virus following allogeneic stem cell transplantation in SIV-infected ART-suppressed macaques.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) from donors lacking C-C chemokine receptor 5 (CCR5Δ32/Δ32) can cure HIV, yet mechanisms remain speculative. To define how alloHSCT mediates HIV cure, we performed MHC-matched alloHSCT in SIV+, anti-retroviral therapy (ART)-suppressed Mauritian cynomolgus macaques (MCMs) and demonstrated that allogeneic immunity was the major driver of reservoir clearance, occurring first in peripheral blood, then peripheral lymph nodes, and finally in mesenteric lymph nodes draining the gastrointestinal tract. While allogeneic immunity could extirpate the latent viral reservoir and did so in two alloHSCT-recipient MCMs that remained aviremic >2.5 years after stopping ART, in other cases, it was insufficient without protection of engrafting cells afforded by CCR5-deficiency, as CCR5-tropic virus spread to donor CD4+ T cells despite full ART suppression. These data demonstrate the individual contributions of allogeneic immunity and CCR5 deficiency to HIV cure and support defining targets of alloimmunity for curative strategies independent of HSCT.

Endothelial cell TRPA1 activity exacerbates cerebral hemorrhage during severe hypertension.

Introduction: Hypoxia-induced dilation of cerebral arteries orchestrated by Ca2+-permeable transient receptor potential ankyrin 1 (TRPA1) cation channels on endothelial cells is neuroprotective during ischemic stroke, but it is unknown if the channel has a similar impact during hemorrhagic stroke. TRPA1 channels are endogenously activated by lipid peroxide metabolites generated by reactive oxygen species (ROS). Uncontrolled hypertension, a primary risk factor for the development of hemorrhagic stroke, is associated with increased ROS production and oxidative stress. Therefore, we hypothesized that TRPA1 channel activity is increased during hemorrhagic stroke. Methods: Severe, chronic hypertension was induced in control (Trpa1 fl/fl) and endothelial cell-specific TRPA1 knockout (Trpa1-ecKO) mice using a combination of chronic angiotensin II administration, a high-salt diet, and the addition of a nitric oxide synthase inhibitor to drinking water. Blood pressure was measured in awake, freely-moving mice using surgically placed radiotelemetry transmitters. TRPA1-dependent cerebral artery dilation was evaluated with pressure myography, and expression of TRPA1 and NADPH oxidase (NOX) isoforms in arteries from both groups was determined using PCR and Western blotting techniques. In addition, ROS generation capacity was evaluated using a lucigenin assay. Histology was performed to examine intracerebral hemorrhage lesion size and location. Results: All animals became hypertensive, and a majority developed intracerebral hemorrhages or died of unknown causes. Baseline blood pressure and responses to the hypertensive stimulus did not differ between groups. Expression of TRPA1 in cerebral arteries from control mice was not altered after 28 days of treatment, but expression of three NOX isoforms and the capacity for ROS generation was increased in hypertensive animals. NOX-dependent activation of TRPA1 channels dilated cerebral arteries from hypertensive animals to a greater extent compared with controls. The number of intracerebral hemorrhage lesions in hypertensive animals did not differ between control and Trpa1-ecKO animals but were significantly smaller in Trpa1-ecKO mice. Morbidity and mortality did not differ between groups. Discussion: We conclude that endothelial cell TRPA1 channel activity increases cerebral blood flow during hypertension resulting in increased extravasation of blood during intracerebral hemorrhage events; however, this effect does not impact overall survival. Our data suggest that blocking TRPA1 channels may not be helpful for treating hypertension-associated hemorrhagic stroke in a clinical setting.

Vulnerable Elder Protection Team: Initial experience of an emergency department-based interdisciplinary elder abuse program.

BACKGROUND: An emergency department (ED) visit provides a unique opportunity to identify elder abuse and initiate intervention, but emergency providers rarely do. To address this, we developed the Vulnerable Elder Protection Team (VEPT), an ED-based interdisciplinary consultation service. We describe our initial experience in the first two years after the program launch. METHODS: We launched VEPT in a large, urban, academic ED/hospital. From 4/3/17 to 4/2/19, we tracked VEPT activations, including patient characteristics, assessment, and interventions. We compared VEPT activations to frequency of elder abuse identification in the ED before VEPT launch. We examined outcomes for patients evaluated by VEPT, including change in living situation at discharge. We assessed ED providers' experiences with VEPT via written surveys and focus groups. RESULTS: During the program's initial two years, VEPT was activated and provided consultation/care to 200 ED patients. Cases included physical abuse (59%), neglect (56%), financial exploitation (32%), verbal/emotional/psychological abuse (25%), and sexual abuse (2%). Sixty-two percent of patients assessed were determined by VEPT to have high or moderate suspicion for elder abuse. Seventy-five percent of these patients had a change in living/housing situation or were discharged with new or additional home services, with 14% discharged to an elder abuse shelter, 39% to a different living/housing situation, and 22% with new or additional home services. ED providers reported that VEPT made them more likely to consider/assess for elder abuse and recognized the value of the expertise and guidance VEPT provided. Ninety-four percent reported believing that there is merit in establishing a VEPT Program in other EDs. CONCLUSION: VEPT was frequently activated and many patients were discharged with changes in living situation and/or additional home services, which may improve safety. Future research is needed to examine longer-term outcomes.

Psychosocial hazards, posttraumatic stress disorder, complex posttraumatic stress disorder, depression, and anxiety in the U.K. rail industry: A cross-sectional study.

This study examined posttraumatic stress disorder (PTSD), complex PTSD, depression, and anxiety among U.K. rail workers. A cross-sectional survey examining exposure to seven psychosocial hazards (bullying/harassment; verbal abuse; physical and sexual assault; and hearing about, seeing the aftermath of, or witnessing a fatality), working conditions, physical health, and the impact of COVID-19 was administered to 3,912 participants. Outcome measures were the ITQ, PHQ-9, and GAD-7. Among trauma-exposed participants, 24.3% met the criteria for PTSD or CPTSD; 38.6% and 29.2% of all participants scored in the moderate-to-severe range on the PHQ-9 and GAD-7, respectively. Data were analyzed using logistic and linear regression. Bullying/harassment was positively associated with GAD-7 scores, f2 = .001, and PTSD and CPTSD, ORs = 1.83-2.02. Hearing about and witnessing a fatality were associated with PTSD and CPTSD, ORs = 1.77-2.10. Poorer ergonomics at work were positively associated with PHQ-9 and GAD-7 scores, f2 = .001. Higher job satisfaction was associated with lower odds of PTSD and CPTSD, ORs = 0.87-0.91, and negatively associated with PHQ-9 and GAD-7 scores, f2 = .008-.01. Work intensity was associated with PTSD and CPTSD, ORs = 1.79-1.83, and positively associated with PHQ-9 and GAD-7 scores, f2 = .02-.03. Reporting more physical health problems was associated with PTSD, OR = 1.07, and positively associated with GAD-7 and PHQ-9 scores, f2 = .008-.01. The results suggest bullying/harassment and work intensity are important variables in employee mental health and could drive future research and industry initiatives.

Characteristics and neuropsychological impact of traumatic brain injury in female prisoners.

Objective: To investigate the characteristics of head injury (HI) and its association with offending behaviour, psychological and neurobehavioral functioning, and cognitive performance in female prisoners.Methods: Using a cross-sectional design, female prisoners in the UK reporting a HI with a loss of consciousness (LOC) over ten minutes (n = 10) were compared with a group without a HI with LOC over ten minutes (n = 41) across a range of measures; including scores on standardized clinical questionnaires and performance-based cognitive assessments. Semi-structured clinical interviews assessed HI and forensic history, with forensic history triangulated against the prison database.Results: Domestic abuse was the most frequently reported cause of HI. The HI with LOC group had been to prison a greater number of times and had committed a greater number violent offences. No significant difference was found on self-reported psychological and neurobehavioral measures, or between the groups' cognitive functioning on neuropsychological tests.Conclusions: Psychosocial factors such as trauma may contribute to higher rates of violent offending and imprisonment in those with a HI with LOC. Domestic abuse is an important factor in HI amongst female prisoners. Forensic screening and interventions need to be designed, adapted and evaluated with consideration of trauma and HI.

Upregulation of Superoxide Dismutase 2 by Astrocytes in the SIV/Macaque Model of HIV-Associated Neurologic Disease.

HIV-associated neurocognitive disorders (HAND) remain prevalent despite implementation of antiretroviral therapy (ART). Development of HAND is linked to mitochondrial dysfunction and oxidative stress in the brain; therefore, upregulation of antioxidant defenses is critical to curtail neuronal damage. Superoxide dismutase 2 (SOD2) is a mitochondrial antioxidant enzyme essential for maintaining cellular viability. We hypothesized that SOD2 was upregulated during retroviral infection. Using a simian immunodeficiency virus (SIV)-infected macaque model of HIV, quantitative PCR showed elevated SOD2 mRNA in cortical gray ([GM], 7.6-fold for SIV vs uninfected) and white matter ([WM], 77-fold for SIV vs uninfected) during SIV infection. Further, SOD2 immunostaining was enhanced in GM and WM from SIV-infected animals. Double immunofluorescence labeling illustrated that SOD2 primarily colocalized with astrocyte marker glial fibrillary acidic protein (GFAP) in SIV-infected animals. Interestingly, in ART-treated SIV-infected animals, brain SOD2 RNA levels were similar to uninfected animals. Additionally, using principal component analysis in a transcriptomic approach, SOD2 and GFAP expression separated SIV-infected from uninfected brain tissue. Projection of these data into a HIV dataset revealed similar expression changes, thereby validating the clinical relevance. Together, our findings suggest that novel SOD2-enhancing therapies may reduce neuroinflammation in ART-treated HIV-infected patients.

The prognostic value of national early warning scores (NEWS) during transfer of care from community settings to hospital: a retrospective service evaluation.

BACKGROUND: The National Early Warning Score (NEWS) calculated from physiological observations provides a simple away to identify and respond to the deteriorating patient. There is increasing interest in the application of NEWS to facilitate referrals from the community. AIM: To establish whether elevated NEWS are associated with adverse outcomes at 5 and 30 days when obtained in a community setting at the time of transfer to an acute setting. DESIGN & SETTING: A retrospective service evaluation was undertaken using a database of emergency admissions to secondary care from two NHS district general hospitals within the South of England between January 2018 and April 2019. METHOD: The performance of NEWS recorded in a community setting to predict death or critical care admission at 5 and 30 days was calculated using established thresholds. RESULTS: 2786 referrals from primary care were analysed. The 5 day and 30 day mortality was 2.2% (1.7 to 2.8) and 7.1% (6.2 to 8.1). The prevalence of the composite outcome was 3.4% (2.8 to 4.2) at 5 days and 8.5% (7.5 to 9.6) at 30 days. The risk of adverse outcomes increased incrementally with increasing NEWS. When calculated at the point of referral from primary care the positive predictive value of death at 5 and 30 days was 15% (95% confidence intervals [CI] = 12 to 19) and 23% (95% CI = 17 to 30) in the high-risk NEWS group. CONCLUSION: Elevated NEWS obtained in the community during the process of emergency admission are associated with adverse outcomes. Communicating NEWS may allow downstream care to be better calibrated to risk.

Utility of the Brain Injury Screening Index in Identifying Female Prisoners With a Traumatic Brain Injury and Associated Cognitive Impairment.

There is a high prevalence of traumatic brain injury (TBI) in prisoners, but screening tools for identifying TBI in female prisoners are not readily available. Using a cross-sectional design, the psychometric properties of the Brain Injury Screening Index (BISI) were investigated in a closed United Kingdom female prison. Purposive sampling comprised 56 females. Assessment included clinical interview, the BISI, self-report measures of mood, and a battery of measures of cognitive functioning. Seven of the 10 clinical indicators on the BISI met test-retest reliability criteria. Two of the three BISI summary variables demonstrated correlations with questionnaires in the hypothesized directions; however, only two BISI variables were associated with cognitive functioning. Findings support further investigation into the validity and reliability of the BISI with a larger sample.

Overexpression of the neuronal human (pro)renin receptor mediates angiotensin II-independent blood pressure regulation in the central nervous system.

Despite advances in antihypertensive therapeutics, at least 15-20% of hypertensive patients have resistant hypertension through mechanisms that remain poorly understood. In this study, we provide a new mechanism for the regulation of blood pressure (BP) in the central nervous system (CNS) by the (pro)renin receptor (PRR), a recently identified component of the renin-angiotensin system that mediates ANG II formation in the CNS. Although PRR also mediates ANG II-independent signaling, the importance of these pathways in BP regulation is unknown. Here, we developed a unique transgenic mouse model overexpressing human PRR (hPRR) specifically in neurons (Syn-hPRR). Intracerebroventricular infusion of human prorenin caused increased BP in Syn-hPRR mice. This BP response was attenuated by a NADPH oxidase (NOX) inhibitor but not by antihypertensive agents that target the renin-angiotensin system. Using a brain-targeted genetic knockdown approach, we found that NOX4 was the key isoform responsible for the prorenin-induced elevation of BP in Syn-hPRR mice. Moreover, inhibition of ERK significantly attenuated the increase in NOX activity and BP induced by human prorenin. Collectively, our findings indicate that an ANG II-independent, PRR-mediated signaling pathway regulates BP in the CNS by a PRR-ERK-NOX4 mechanism. NEW & NOTEWORTHY This study characterizes a new transgenic mouse model with overexpression of the human (pro)renin receptor in neurons and demonstrated a novel angiotensin II-independent mechanism mediated by human prorenin and the (pro)renin receptor in the central regulation of blood pressure.

To stand back or step in? Exploring the responses of employees who observe workplace bullying.

Bullying remains a pervasive problem in healthcare, and evidence suggests systems in place are not utilised due to perceptions of ineffectiveness and inequity. This study examines bystander responses to bullying and factors that influence decisions to intervene. We explore relationships between bystanders' perceptions of psychological safety across three levels (organisation, supervisor and colleague) and reactions to witnessing bullying. We suggest psychological safety would be positively associated with the decision to intervene. Findings indicate the most pervasive reaction to witnessing incidents of bullying is to discuss with colleagues, a low-involvement reaction. We find perceptions of supervisory and organisational safety/support are positively related to high-involvement decisions such as formal reporting of the incidents, highlighting the importance of support from those in power. However, perceptions of collegial support may lead to low-involvement responses, which risk reinforcing and underpinning dysfunctional organisational dynamics by providing informal social and emotional responses that may substitute more formal organisational responses to this persistent problem. This study highlights the importance of support from individuals in power if bystanders are to feel comfortable making high-involvement interventions.

Unitary TRPV3 channel Ca2+ influx events elicit endothelium-dependent dilation of cerebral parenchymal arterioles.

Cerebral parenchymal arterioles (PA) regulate blood flow between pial arteries on the surface of the brain and the deeper microcirculation. Regulation of PA contractility differs from that of pial arteries and is not completely understood. Here, we investigated the hypothesis that the Ca(2+) permeable vanilloid transient receptor potential (TRPV) channel TRPV3 can mediate endothelium-dependent dilation of cerebral PA. Using total internal reflection fluorescence microscopy (TIRFM), we found that carvacrol, a monoterpenoid compound derived from oregano, increased the frequency of unitary Ca(2+) influx events through TRPV3 channels (TRPV3 sparklets) in endothelial cells from pial arteries and PAs. Carvacrol-induced TRPV3 sparklets were inhibited by the selective TRPV3 blocker isopentenyl pyrophosphate (IPP). TRPV3 sparklets have a greater unitary amplitude (ΔF/F0 = 0.20) than previously characterized TRPV4 (ΔF/F0 = 0.06) or TRPA1 (ΔF/F0 = 0.13) sparklets, suggesting that TRPV3-mediated Ca(2+) influx could have a robust influence on cerebrovascular tone. In pressure myography experiments, carvacrol caused dilation of cerebral PA that was blocked by IPP. Carvacrol-induced dilation was nearly abolished by removal of the endothelium and block of intermediate (IK) and small-conductance Ca(2+)-activated K(+) (SK) channels. Together, these data suggest that TRPV3 sparklets cause dilation of cerebral parenchymal arterioles by activating IK and SK channels in the endothelium.

Localized TRPA1 channel Ca2+ signals stimulated by reactive oxygen species promote cerebral artery dilation.

Reactive oxygen species (ROS) can have divergent effects in cerebral and peripheral circulations. We found that Ca(2+)-permeable transient receptor potential ankyrin 1 (TRPA1) channels were present and colocalized with NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase 2 (NOX2), a major source of ROS, in the endothelium of cerebral arteries but not in other vascular beds. We recorded and characterized ROS-triggered Ca(2+) signals representing Ca(2+) influx through single TRPA1 channels, which we called "TRPA1 sparklets." TRPA1 sparklet activity was low under basal conditions but was stimulated by NOX-generated ROS. Ca(2+) entry during a single TRPA1 sparklet was twice that of a TRPV4 sparklet and ~200 times that of an L-type Ca(2+) channel sparklet. TRPA1 sparklets representing the simultaneous opening of two TRPA1 channels were more common in endothelial cells than in human embryonic kidney (HEK) 293 cells expressing TRPA1. The NOX-induced TRPA1 sparklets activated intermediate-conductance, Ca(2+)-sensitive K(+) channels, resulting in smooth muscle hyperpolarization and vasodilation. NOX-induced activation of TRPA1 sparklets and vasodilation required generation of hydrogen peroxide and lipid-peroxidizing hydroxyl radicals as intermediates. 4-Hydroxy-nonenal, a metabolite of lipid peroxidation, also increased TRPA1 sparklet frequency and dilated cerebral arteries. These data suggest that in the cerebral circulation, lipid peroxidation metabolites generated by ROS activate Ca(2+) influx through TRPA1 channels in the endothelium of cerebral arteries to cause dilation.

Intracerebroventricular infusion of the (Pro)renin receptor antagonist PRO20 attenuates deoxycorticosterone acetate-salt-induced hypertension.

We previously reported that binding of prorenin to the (pro)renin receptor (PRR) plays a major role in brain angiotensin II formation and the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Here, we designed and developed an antagonistic peptide, PRO20, to block prorenin binding to the PRR. Fluorescently labeled PRO20 bound to both mouse and human brain tissues with dissociation constants of 4.4 and 1.8 nmol/L, respectively. This binding was blocked by coincubation with prorenin and was diminished in brains of neuron-specific PRR-knockout mice, indicating specificity of PRO20 for PRR. In cultured human neuroblastoma cells, PRO20 blocked prorenin-induced calcium influx in a concentration- and AT(1) receptor-dependent manner. Intracerebroventricular infusion of PRO20 dose-dependently inhibited prorenin-induced hypertension in C57Bl6/J mice. Furthermore, acute intracerebroventricular infusion of PRO20 reduced blood pressure in both DOCA-salt and genetically hypertensive mice. Chronic intracerebroventricular infusion of PRO20 attenuated the development of hypertension and the increase in brain hypothalamic angiotensin II levels induced by DOCA-salt. In addition, chronic intracerebroventricular infusion of PRO20 improved autonomic function and spontaneous baroreflex sensitivity in mice treated with DOCA-salt. In summary, PRO20 binds to both mouse and human PRRs and decreases angiotensin II formation and hypertension induced by either prorenin or DOCA-salt. Our findings highlight the value of the novel PRR antagonist, PRO20, as a lead compound for a novel class of antihypertensive agents and as a research tool to establish the validity of brain PRR antagonism as a strategy for treating hypertension.

The prevalence and management of poor sleep quality in a secondary care mental health population.

STUDY OBJECTIVES: Poor sleep quality, particularly insomnia, has been identified as a frequent problem among individuals with mental health difficulties. Comorbid sleep difficulties adversely affect quality of life and functioning, and have been associated with the causation and maintenance of a number of psychiatric disorders, as well as increasing the risk of relapse. The study objectives were to ascertain clinician knowledge related to insomnia, investigate sleep quality among service users in a community mental health setting in the UK, and evaluate service provision of evidence-based interventions for sleep difficulties. METHODS: A cross-sectional design was used. Nineteen clinicians completed a questionnaire on their clinical practice. Seventy-three service users completed the Pittsburgh Sleep Quality Index and provided self-report data on interventions received and associated satisfaction. RESULTS: Clinical staff demonstrated deficits in knowledge of insomnia symptomatology. Sixty-four percent (95% CI 54% to 74%) of service users were identified as poor sleepers on the PSQI. Sixty-one percent of poor sleepers had not been offered support for sleep difficulties. The most common support received was prescribed psychotropic medication (32%). Cognitive behavioral therapy was the intervention rated as most helpful but was only received by 6%. CONCLUSIONS: This study highlights inadequaciesin providing evidence-based interventions for sleep difficulties. Key recommendations include training clinicians in the identification of sleep difficulties and provision of evidence-based interventions, provision of cost-effective transdiagnostic group interventions, and formalizing assessment and treatment pathways for service users with sleep difficulties.

A PLCγ1-dependent, force-sensitive signaling network in the myogenic constriction of cerebral arteries.

Maintaining constant blood flow in the face of fluctuations in blood pressure is a critical autoregulatory feature of cerebral arteries. An increase in pressure within the artery lumen causes the vessel to constrict through depolarization and contraction of the encircling smooth muscle cells. This pressure-sensing mechanism involves activation of two types of transient receptor potential (TRP) channels: TRPC6 and TRPM4. We provide evidence that the activation of the γ1 isoform of phospholipase C (PLCγ1) is critical for pressure sensing in cerebral arteries. Inositol 1,4,5-trisphosphate (IP3), generated by PLCγ1 in response to pressure, sensitized IP3 receptors (IP3Rs) to Ca(2+) influx mediated by the mechanosensitive TRPC6 channel, synergistically increasing IP3R-mediated Ca(2+) release to activate TRPM4 currents, leading to smooth muscle depolarization and constriction of isolated cerebral arteries. Proximity ligation assays demonstrated colocalization of PLCγ1 and TRPC6 with TRPM4, suggesting the presence of a force-sensitive, local signaling network comprising PLCγ1, TRPC6, TRPM4, and IP3Rs. Src tyrosine kinase activity was necessary for stretch-induced TRPM4 activation and myogenic constriction, consistent with the ability of Src to activate PLCγ isoforms. We conclude that contraction of cerebral artery smooth muscle cells requires the integration of pressure-sensing signaling pathways and their convergence on IP3Rs, which mediate localized Ca(2+)-dependent depolarization through the activation of TRPM4.

Calcineurin/nuclear factor of activated T cells-coupled vanilliod transient receptor potential channel 4 ca2+ sparklets stimulate airway smooth muscle cell proliferation.

Proliferation of airway smooth muscle cells (ASMCs) contributes to the remodeling and irreversible obstruction of airways during severe asthma, but the mechanisms underlying this disease process are poorly understood. Here we tested the hypothesis that Ca(2+) influx through the vanilliod transient receptor potential channel (TRPV) 4 stimulates ASMC proliferation. We found that synthetic and endogenous TRPV4 agonists increase proliferation of primary ASMCs. Furthermore, we demonstrate that Ca(2+) influx through individual TRPV4 channels produces Ca(2+) microdomains in ASMCs, called "TRPV4 Ca(2+) sparklets." We also show that TRPV4 channels colocalize with the Ca(2+)/calmodulin-dependent protein phosphatase calcineurin in ASMCs. Activated calcineurin dephosphorylates nuclear factor of activated T cells (NFAT) transcription factors cytosolic (c) to allow nuclear translocation and activation of synthetic transcriptional pathways. We show that ASMC proliferation in response to TRPV4 activity is associated with calcineurin-dependent nuclear translocation of the NFATc3 isoform tagged with green florescent protein. Our findings suggest that Ca(2+) microdomains created by TRPV4 Ca(2+) sparklets activate calcineurin to stimulate nuclear translocation of NFAT and ASMC proliferation. These findings further suggest that inhibition of TRPV4 could diminish asthma-induced airway remodeling.