A5032038585- Cerebrovascular and genetic disorders
- Nitric Oxide and Endothelin Effects
- Ion channel regulation and function
- Neurological Disease Mechanisms and Treatments
- Neuroscience and Neuropharmacology Research
- Barrier Structure and Function Studies
- Traumatic Brain Injury and Neurovascular Disturbances
- Cerebrovascular and Carotid Artery Diseases
- Neuroinflammation and Neurodegeneration Mechanisms
- Protease and Inhibitor Mechanisms
- Cell Adhesion Molecules Research
- Neuroscience of respiration and sleep
- Cardiac electrophysiology and arrhythmias
- Acute Ischemic Stroke Management
- Photoreceptor and optogenetics research
- S100 Proteins and Annexins
- Alzheimer's disease research and treatments
- Receptor Mechanisms and Signaling
- Ion Channels and Receptors
- Stress Responses and Cortisol
- Eicosanoids and Hypertension Pharmacology
- Calcium signaling and nucleotide metabolism
- Heart Rate Variability and Autonomic Control
- Metalloenzymes and iron-sulfur proteins
- Intracranial Aneurysms: Treatment and Complications
University of Colorado Anschutz Medical Campus
2019-2025
University of Colorado Denver
2023
University of Vermont
2011-2021
Cleveland Clinic Lerner College of Medicine
2021
La Trobe University
2018
University of Iowa
2018
Université de Bordeaux
2006-2011
Institut des Maladies Neurodégénératives
2011
Centre National de la Recherche Scientifique
2006-2011
Karolinska Institutet
2008
The signaling pathway that links the sensing of increased blood pressure to constriction in cerebral arteries is delineated.
Significance Years before the emergence of infarctions or significant cognitive decline, patients with cerebral small vessel disease (SVD) show a deterioration in ability brain to augment blood flow locally response increases neuronal activity (functional hyperemia). Using well-characterized genetic mouse model hereditary form SVD, we determined molecular defect at play capillary endothelial cells. We found that SVD is associated reduced synthesis phospholipid PIP 2 , which prevents Kir2.1...
Microglia, the resident immune cells of central nervous system, are intimately involved in brain's most basic processes, from pruning neural synapses during development to preventing excessive neuronal activity throughout life. Studies have reported both helpful and harmful roles for microglia at blood-brain barrier (BBB) context disease. However, less is known about microglia-endothelial cell interactions healthy brain. To investigate role a BBB, we used colony-stimulating factor 1 receptor...
Acidosis is a powerful vasodilator signal in the brain circulation. However, mechanisms by which this response occurs are not well understood, particularly cerebral microcirculation. One important mechanism to dilate (pial) arteries activation of large-conductance, calcium-sensitive potassium (BK(Ca)) channels local Ca(2+) signals (Ca(2+) sparks) through ryanodine receptors (RyRs). role pathway microcirculation known.The objectives study were determine acidosis dilates parenchymal arterioles...
Significance Small vessel disease (SVD) of the brain refers to a group pathological processes leading cerebral lesions, cognitive decline, and stroke. Despite importance SVD, there is no specific treatment, mainly due limited understanding pathogenesis. Using recently developed mouse model autosomal dominant arteriopathy with subcortical infarcts leukoencephalopathy, hereditary form we determined basis altered artery function at an early stage progression. We found that cerebrospecific...
Significance Capillaries, the smallest blood vessels, mediate on-demand delivery of oxygen and nutrients required to support function active cells throughout brain. But how flow is directed in brain regions satisfy their energy needs poorly understood. We demonstrate that plasma membrane phospholipid, PIP 2 , fundamental sustaining activity inwardly rectifying potassium channels—the molecular feature allows capillary endothelial sense ongoing neuronal trigger an increase local flow. further...
Significance When neurons become active, they signal to local arterioles via intermediate glial cells, called astrocytes, evoke dilation. This increases blood flow and provides the oxygen glucose necessary support ongoing neuronal function. process is termed neurovascular coupling. We demonstrate that chronic stress—which a contributing factor for many diseases—impairs coupling in amygdala, region involved stressor processing. Our results further indicate this dysfunction due loss of...
Cerebral small vessel disease (SVD) is a leading cause of stroke and dementia. CADASIL, an inherited SVD, alters cerebral artery function, compromising blood flow to the working brain. TIMP3 (tissue inhibitor metalloproteinase 3) accumulation in vascular extracellular matrix CADASIL key contributor cerebrovascular dysfunction. However, linkage between elevated compromised (CBF) remains unknown. Here, we show that acts through inhibition metalloprotease ADAM17 HB-EGF regulate arterial tone...
Neuronal activity leads to an increase in local cerebral blood flow (CBF) allow adequate supply of oxygen and nutrients 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 interstitial induce rapid robust dilations upstream parenchymal arterioles, suggesting key role cECs NVC. The requirements this signal conduction remain elusive. Here, we...
Spontaneous deep intracerebral hemorrhage (ICH) is a devastating subtype of stroke without specific treatments. It has been thought that smooth muscle cell (SMC) degeneration at the site arteriolar wall rupture may be sufficient to cause hemorrhage. However, ICHs are rare in some aggressive small vessel diseases characterized by significant SMC degeneration. Here we hypothesized second cellular defect required for occurrence ICH.We studied genetic model spontaneous ICH using Col4a1+/G498V...
Dementia resulting from small vessel diseases (SVDs) of the brain is an emerging epidemic for which there no treatment. Hypertension major risk factor SVDs, but how hypertension damages microcirculation unclear. Here, we show that chronic in a mouse model progressively disrupts on-demand delivery blood to metabolically active areas (functional hyperemia) through diminished activity capillary endothelial cell inward-rectifier potassium channel, Kir2.1. Despite similar efficacy reducing...
It has been proposed that prostaglandin E(2) (PGE(2)) is released from astrocytic endfeet to dilate parenchymal arterioles through activation of prostanoid (EP(4)) receptors during neurovascular coupling. However, the direct effects PGE(2) on isolated have not tested. Here, we examined diameter pressurized rat and mouse brain. Contrary prevailing assumption, found (0.1, 1, 5 μmol/L) constricted rather than dilated arterioles. Vasoconstriction was prevented by inhibitors EP(1) receptors....
Vascular aging fundamentally contributes to large and small vessel disease. Despite the importance of such changes for brain function, mechanisms that mediate are poorly defined. We explored underlie with age, testing hypothesis ROCK (Rho kinase) plays an important role. In C57BL/6 mice, baseline diameters isolated pressurized parenchymal arterioles were similar in adult (4–5 month) old mice (22±1 month; ≈15±1 µm). Endothelium-dependent dilation was impaired compared adults a...
Abstract Rapid restoration of blood flow is critical in treating acute ischemic stroke. Current thrombolytic therapies using tissue plasminogen activator (tPA) are limited by low recanalization rates and risks off‐target bleeding. Here, we demonstrate that a remarkably simple adjustment—using micrometer‐scale rather than sub‐micrometer particles to immobilize tPA—fundamentally improves thrombolysis. By merely increasing the particle diameter from 0.1 1.0 μm, achieve dramatic shift lysis...
VasoTracker 2 is an open-source platform for studying blood vessel dynamics, featuring versatile diameter-tracking software and complementary low-cost hardware components. This system surpasses existing tools through accessible, high-resolution analysis across multiple imaging modalities, enabling comprehensive assessment of vascular dynamics in both real-time pre-recorded experiments. Advanced algorithms enable multi-point diameter tracking branched vessels, automated pressure-response...
Cerebral autoregulation ensures constant blood flow, an essential condition of brain health. A fundamental parameter the circulation is dynamic regulation microvessel diameter to allow for adjustments in resistance pressure changes. Pericytes are a family mural cells that wrap around capillary endothelium and contribute control diameter. We sought determine whether how pericytes constrict response elevation with vivo two-photon microscopy, electrophysiology, ex arteriolar-capillary myography...
Intracerebral parenchymal arterioles (PAs), which include arterioles, penetrating and pre-capillary are high resistance blood vessels branching out from pial arteries diving into the brain parenchyma. Individual PA perfuse a discrete cylindrical territory of parenchyma neurons contained within. These central player in regulation cerebral flow both globally (cerebrovascular autoregulation) locally (functional hyperemia). PAs part neurovascular unit, structure that matches regional to...
Prostaglandin E 2 (PGE ) has been widely proposed to mediate neurovascular coupling by dilating brain parenchymal arterioles through activation of prostanoid EP4 receptors. However, our previous report that direct application PGE induces an EP1-mediated constriction strongly argues against its action on during coupling, the mechanisms sustaining functional hyperemia. Recent advances have highlighted role capillaries in sensing neuronal activity and propagating vasodilatory signals upstream...
Our aim was to explore the nutritional consequences of functional variations in hypothalamic–pituitary–adrenocortical (HPA) axis rats. We first aimed compare HPA activity and reactivity stress between Fischer 344 (F344) LOU/C (LOU) strains that differ food behavior metabolism. When compared with F344 rats, LOU rats showed lower corticosterone (Cort) levels across circadian cycle after restraint stress. Then, we effects adrenalectomized (ADX) Cort substitution ADX on intake, body weight gain,...
Alternative splicing of ryanodine receptor subtype 3 (RYR3) may generate a short isoform (RYR3S) without channel function and functional full-length (RYR3L). The RYR3S has been shown to negatively regulate the native RYR2 in smooth muscle cells as well RYR3L when both isoforms were coexpressed HEK-293 cells. Mouse myometrium expresses only RYR3 subtype, but role obtained by alternative their activation cADP-ribose during pregnancy have never investigated. Here, we show that are...
Gravity has a structural role for living systems. Tissue development, architecture, and organization are modified when the gravity vector is changed. In particular, microgravity induces redistribution of blood volume thus pressure in astronaut body, abolishing an upright gradient, inducing orthostatic hypotension. The present study was designed to investigate whether isolated vascular smooth muscle cells directly sensitive altered gravitational forces and, second, sustained changes act on...