K channel-dependent electrical signaling links capillary pericytes to arterioles during neurovascular coupling.

The brain has evolved mechanisms to dynamically modify blood flow, enabling the timely delivery of energy substrates in response to local metabolic demands. Several such neurovascular coupling (NVC) mechanisms have been identified, but the vascular signal transduction and transmission mechanisms that enable dilation of penetrating arterioles (PAs) remote from sites of increased neuronal activity are unclear. Given the exponential relationship between vessel diameter and blood flow, tight control of arteriole membrane potential and diameter is a crucial aspect of NVC.

Endothelial Piezo1 channel mediates mechano-feedback control of brain blood flow.

Hyperemia in response to neural activity is essential for brain health. A hyperemic response delivers O and nutrients, clears metabolic waste, and concomitantly exposes cerebrovascular endothelial cells to hemodynamic forces. While neurovascular research has primarily centered on the front end of hyperemia-neuronal activity-to-vascular response-the mechanical consequences of hyperemia have gone largely unexplored.

Pathophysiologic abnormalities in transgenic mice carrying the Alzheimer disease PSEN1 Δ440 mutation.

Mutations in PSEN1 were first discovered as a cause of Alzheimer's disease (AD) in 1995, yet the mechanism(s) by which the mutations cause disease still remains unknown. The generation of novel mouse models assessing the effects of different mutations could aid in this endeavor. Here we report on transgenic mouse lines made with the Δ440 PSEN1 mutation that causes AD with parkinsonism:- two expressing the un-tagged human protein and two expressing a HA-tagged version.

Electro-metabolic signaling.

Precise matching of energy substrate delivery to local metabolic needs is essential for the health and function of all tissues. Here, we outline a mechanistic framework for understanding this critical process, which we refer to as electro-metabolic signaling (EMS). All tissues exhibit changes in metabolism over varying spatiotemporal scales and have widely varying energetic needs and reserves.

Pericytes and the Control of Blood Flow in Brain and Heart.

Pericytes, attached to the surface of capillaries, play an important role in regulating local blood flow. Using optogenetic tools and genetically encoded reporters in conjunction with confocal and multiphoton imaging techniques, the 3D structure, anatomical organization, and physiology of pericytes have recently been the subject of detailed examination. This work has revealed novel functions of pericytes and morphological features such as tunneling nanotubes in brain and tunneling microtubes in heart.

Brain capillary pericytes are metabolic sentinels that control blood flow through a K channel-dependent energy switch.

Despite the abundance of capillary thin-strand pericytes and their proximity to neurons and glia, little is known of the contributions of these cells to the control of brain hemodynamics. We demonstrate that the pharmacological activation of thin-strand pericyte K channels profoundly hyperpolarizes these cells, dilates upstream penetrating arterioles and arteriole-proximate capillaries, and increases capillary blood flow. Focal stimulation of pericytes with a K channel agonist is sufficient to evoke this response, mediated via K2.

Evaluation of the Victorian Healthy Homes Program: protocol for a randomised controlled trial.

Introduction: The evaluation of the Victorian Healthy Homes Program (VHHP) will generate evidence about the efficacy and cost-effectiveness of home upgrades to improve thermal comfort, reduce energy use and produce health and economic benefits to vulnerable households in Victoria, Australia.

Methods And Analysis: The VHHP evaluation will use a staggered, parallel group clustered randomised controlled trial to test the home energy intervention in 1000 households. All households will receive the intervention either before (intervention group) or after (control group) winter (defined as 22 June to 21 September).

Differential restoration of functional hyperemia by antihypertensive drug classes in hypertension-related cerebral small vessel disease.

Dementia resulting from small vessel diseases (SVDs) of the brain is an emerging epidemic for which there is no treatment. Hypertension is the major risk factor for SVDs, but how hypertension damages the brain microcirculation is unclear. Here, we show that chronic hypertension in a mouse model progressively disrupts on-demand delivery of blood to metabolically active areas of the brain (functional hyperemia) through diminished activity of the capillary endothelial cell inward-rectifier potassium channel, Kir2.

Local IP receptor-mediated Ca signals compound to direct blood flow in brain capillaries.

Healthy brain function depends on the finely tuned spatial and temporal delivery of blood-borne nutrients to active neurons via the vast, dense capillary network. Here, using in vivo imaging in anesthetized mice, we reveal that brain capillary endothelial cells control blood flow through a hierarchy of IP receptor-mediated Ca events, ranging from small, subsecond protoevents, reflecting Ca release through a small number of channels, to high-amplitude, sustained (up to ~1 min) compound events mediated by large clusters of channels. These frequent (~5000 events/s per microliter of cortex) Ca signals are driven by neuronal activity, which engages G protein-coupled receptor signaling, and are enhanced by Ca entry through TRPV4 channels.

PIP corrects cerebral blood flow deficits in small vessel disease by rescuing capillary Kir2.1 activity.

Cerebral small vessel diseases (SVDs) are a central link between stroke and dementia-two comorbidities without specific treatments. Despite the emerging consensus that SVDs are initiated in the endothelium, the early mechanisms remain largely unknown. Deficits in on-demand delivery of blood to active brain regions (functional hyperemia) are early manifestations of the underlying pathogenesis.

The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes.

Brain pericytes reside on the abluminal surface of capillaries, and their processes cover ~90% of the length of the capillary bed. These cells were first described almost 150 years ago (Eberth, 1871; Rouget, 1873) and have been the subject of intense experimental scrutiny in recent years, but their physiological roles remain uncertain and little is known of the complement of signaling elements that they employ to carry out their functions. In this review, we synthesize functional data with single-cell RNAseq screens to explore the ion channel and G protein-coupled receptor (GPCR) toolkit of mesh and thin-strand pericytes of the brain, with the aim of providing a framework for deeper explorations of the molecular mechanisms that govern pericyte physiology.

Impaired capillary-to-arteriolar electrical signaling after traumatic brain injury.

Traumatic brain injury (TBI) acutely impairs dynamic regulation of local cerebral blood flow, but long-term (>72 h) effects on functional hyperemia are unknown. Functional hyperemia depends on capillary endothelial cell inward rectifier potassium channels (Kir2.1) responding to potassium (K) released during neuronal activity to produce a regenerative, hyperpolarizing electrical signal that propagates from capillaries to dilate upstream penetrating arterioles.

Vascular control of the CO/H-dependent drive to breathe.

Respiratory chemoreceptors regulate breathing in response to changes in tissue CO/H. Blood flow is a fundamental determinant of tissue CO/H, yet little is known regarding how regulation of vascular tone in chemoreceptor regions contributes to respiratory behavior. Previously, we showed in rat that CO/H-vasoconstriction in the retrotrapezoid nucleus (RTN) supports chemoreception by a purinergic-dependent mechanism (Hawkins et al.

The capillary Kir channel as sensor and amplifier of neuronal signals: Modeling insights on K-mediated neurovascular communication.

Neuronal activity leads to an increase in local cerebral blood flow (CBF) to allow adequate supply of oxygen and nutrients to active neurons, a process termed neurovascular coupling (NVC). We have previously shown that capillary endothelial cell (cEC) inwardly rectifying K (Kir) channels can sense neuronally evoked increases in interstitial K and induce rapid and robust dilations of upstream parenchymal arterioles, suggesting a key role of cECs in NVC. The requirements of this signal conduction remain elusive.

Ion channels in capillary endothelium.

Vascular beds are anatomically and functionally compartmentalized into arteries, capillaries, and veins. The bulk of the vasculature consists of the dense, anastomosing capillary network, composed of capillary endothelial cells (cECs) that are intimately associated with the parenchyma. Despite their abundance, the ion channel expression and function and Ca signaling behaviors of capillaries have only recently begun to be explored in detail.

The use of an 'acclimatisation' heatwave measure to compare temperature-related demand for emergency services in Australia, Botswana, Netherlands, Pakistan, and USA.

Background: Heatwaves have been linked to increased risk of mortality and morbidity and are projected to increase in frequency and intensity due to climate change. The current study uses emergency department (ED) data from Australia, Botswana, Netherlands, Pakistan, and the United States of America to evaluate the impact of heatwaves on ED attendances, admissions and mortality.

Methods: Routinely collected time series data were obtained from 18 hospitals.

PIP depletion promotes TRPV4 channel activity in mouse brain capillary endothelial cells.

We recently reported that the inward-rectifier Kir2.1 channel in brain capillary endothelial cells (cECs) plays a major role in neurovascular coupling (NVC) by mediating a neuronal activity-dependent, propagating vasodilatory (hyperpolarizing) signal. We further demonstrated that Kir2.

The prevalence of persistence and related health status: An analysis of persistently high healthcare costs in the short term and medium term.

Understanding whether high healthcare costs for individuals persist over time is critical for the development of policies that aim to reduce the prevalence of high cost patients. And while high healthcare costs will occur in any given year based on the prevalence of certain morbidities and acute conditions, a large random component of the distribution means that it is rarely the same people driving the bulk of healthcare expenditures. Using administrative data for over 250,000 Australian residents for the years between 2006 and 2011, we analyse the persistence of high annual healthcare costs.

Supplier-induced demand for urgent after-hours primary care services.

Australia is one of nine Organisation for Economic Co-operation and Development (OECD) countries that utilise deputising services to provide after-hours primary care. While the provision of this service is supposed to be on behalf of regular general practitioners, businesses have adapted to the financial incentives on offer and are directly advertising their services to consumers emphasising patient convenience and no copayments. The introduction of corporate entities has changed the way that deputising services operate.

Endothelial GqPCR activity controls capillary electrical signaling and brain blood flow through PIP depletion.

Brain capillaries play a critical role in sensing neural activity and translating it into dynamic changes in cerebral blood flow to serve the metabolic needs of the brain. The molecular cornerstone of this mechanism is the capillary endothelial cell inward rectifier K (Kir2.1) channel, which is activated by neuronal activity-dependent increases in external K concentration, producing a propagating hyperpolarizing electrical signal that dilates upstream arterioles.