A5046269285- Nitric Oxide and Endothelin Effects
- Connexins and lens biology
- Sphingolipid Metabolism and Signaling
- Traumatic Brain Injury and Neurovascular Disturbances
- Protein Kinase Regulation and GTPase Signaling
- Intracranial Aneurysms: Treatment and Complications
- Heat shock proteins research
- Ion channel regulation and function
- Neuroinflammation and Neurodegeneration Mechanisms
- Receptor Mechanisms and Signaling
- Cystic Fibrosis Research Advances
- Cardiac Arrest and Resuscitation
- Intracerebral and Subarachnoid Hemorrhage Research
- Cardiac Ischemia and Reperfusion
- Vestibular and auditory disorders
- Cardiovascular Health and Disease Prevention
- Circadian rhythm and melatonin
- Cellular transport and secretion
- Cerebrospinal fluid and hydrocephalus
- Thermoregulation and physiological responses
- Glaucoma and retinal disorders
- Nicotinic Acetylcholine Receptors Study
- Atherosclerosis and Cardiovascular Diseases
- Hearing, Cochlea, Tinnitus, Genetics
- Heart Rate Variability and Autonomic Control
University of Toronto
2012-2024
Ted Rogers Centre for Heart Research
2019-2024
Canada Research Chairs
2007-2017
St. Michael's Hospital
2012-2016
Max Planck Institute for Heart and Lung Research
2015
Tokushima University
2015
Sunnybrook Health Science Centre
2015
Engelhardt Institute of Molecular Biology
2015
Lomonosov Moscow State University
2015
Princess Margaret Cancer Centre
2015
The S1P(2) receptor is a member of family G protein-coupled receptors that bind the extracellular sphingolipid metabolite sphingosine 1-phosphate with high affinity. widely expressed and linked to multiple protein signaling pathways, but its physiological function has remained elusive. Here we have demonstrated expression essential for proper functioning auditory vestibular systems. Auditory brainstem response analysis revealed receptor-null mice were deaf by one month age. These null...
Septic patients have low plasma ascorbate concentrations and compromised microvascular perfusion. The purpose of the present experiments was to determine whether improves capillary function in volume-resuscitated sepsis. Cecal ligation perforation (CLP) performed on male Sprague-Dawley rats. concentration urine, mean arterial blood pressure, density continuously perfused capillaries extensor digitorum longus muscle were measured 24 h after surgery. CLP caused a 50% decrease (from 56 +/- 4 29...
Sphingosine-1-phosphate (S1P), which mediates pleiotropic actions within the vascular system, is a prominent regulator of microvascular tone. By virtue its S1P-degrading function, we hypothesized that S1P-phosphohydrolase 1 (SPP1) an important tone in resistance arteries. Hamster gracilis muscle arteries express mRNA encoding SPP1. Overexpression SPP1 (via transfection SPP1(wt)) reduced resting tone, Ca2+ sensitivity, and myogenic vasoconstriction, whereas expression (antisense...
Background and Purpose— We sought to demonstrate that tumor necrosis factor (TNF)-α, via sphingosine-1-phosphate signaling, has the potential alter cochlear blood flow thus, cause ischemic hearing loss. Methods— performed intravital fluorescence microscopy measure capillary diameter in anesthetized guinea pigs. To ex vivo, beds from gerbil spiral ligament were isolated lateral wall maintained an organ bath. Isolated modiolar arteries, transfected culture, used calcium sensitivity...
Background— Sphingosine-1-phosphate (S1P) signaling is a central regulator of resistance artery tone. Therefore, S1P levels need to be tightly controlled through the delicate interplay its generating enzyme sphingosine kinase 1 and functional antagonist phosphohydrolase-1. The intracellular localization phosphohydrolase-1 necessitates import extracellular into compartment before degradation. present investigation proposes that cystic fibrosis transmembrane conductance transports hence...
Cells sense and respond to changes in oxygen concentration through gene regulatory processes that are fundamental survival. Surprisingly, little is known about how anemia affects hypoxia signaling. Because nitric oxide synthases (NOSs) figure prominently the cellular responses acute hypoxia, we defined effects of NOS deficiency anemia. In contrast endothelial or inducible deficiency, neuronal (nNOS) −/− mice demonstrated increased mortality during Unlike wild-type (WT) animals, did not...
Background— Heart failure is associated with neurological deficits, including cognitive dysfunction. However, the molecular mechanisms underlying reduced cerebral blood flow in early stages of heart failure, particularly when pressure minimally affected, are not known. Methods and Results— Using a myocardial infarction model mice, we demonstrate tumor necrosis factor-α (TNFα)–dependent enhancement posterior artery tone that reduces before any overt changes brain structure function. TNFα...
Background and Purpose— Subarachnoid hemorrhage (SAH) is a complex stroke subtype characterized by an initial brain injury, followed delayed cerebrovascular constriction ischemia. Current therapeutic strategies nonselectively curtail exacerbated constriction, which necessarily disrupts the essential protective process of cerebral blood flow autoregulation. This study identifies smooth muscle cell autocrine/paracrine signaling network that augments myogenic tone in murine model experimental...
Abstract Tumour necrosis factor (TNF) is a ubiquitously expressed cytokine with functions beyond the immune system. In several diseases, induction of TNF expression in resistance artery smooth muscle cells enhances microvascular myogenic vasoconstriction and perturbs blood flow. This pathological role prompted our hypothesis that constitutively regulates signalling systemic haemodynamics under non-pathological settings. Here we show acutely deleting gene or pharmacologically scavenging...
Heart failure (HF) and subarachnoid hemorrhage (SAH) chronically reduce cerebral perfusion, which negatively affects clinical outcome. This work demonstrates a strong relationship between artery cystic fibrosis transmembrane conductance regulator (CFTR) expression altered cerebrovascular reactivity in HF SAH. In SAH, CFTR corrector compounds (C18 or lumacaftor) normalize pathological alterations expression, vascular reactivity, without affecting systemic hemodynamic parameters. normalization...
Given the roles proposed for gap junctional intercellular communication in neuronal differentiation and growth control, we examined effects of connexin43 (Cx43) expression a neuroblastoma cell line. A vesicular stomatitis virus G protein (VSVG)-pseudotyped retrovector was engineered to co-express green fluorescent (GFP) Cx43 communication-deficient neuro-2a (N2a) The 293 GPG packaging line used produce VSVG-pseudotyped retrovectors coding GFP, Cx43, or chimeric Cx43·GFP fusion protein. titer...
Our recent in vitro study (Lidington et al. J Cell Physiol 185: 117–125, 2000) suggested that lipopolysaccharide (LPS) reduces communication along blood vessels. The present investigation extended this to determine whether any effect of LPS and/or inflammatory cytokines [tumor necrosis factor-α, interleukin (IL)-1β, and IL-6] on endothelial cell coupling could also be demonstrated for an arteriolar conducted response vivo. Using electrophysiological approach monolayers microvascular cells,...
Gap junctions are intercellular channels that provide direct passage of small molecules between adjacent cells. In pancreatic acini, the connexin26(Cx26) and connexin32 (Cx32) proteins form functional coordinate secretion digestive enzymes. Although function Cx26/Cx32 gap well characterized, regulatory circuits control spatial temporal expression patterns these connexin genes not known. an effort to identify molecular pathways regulate gene expression, we examined Cx26 Cx32 activities in...
Abstract Gap junction intercellular communication (GJIC) plays a significant role in the vascular system. Regulation of GJIC is dynamic process, with alterations connexin (Cx) protein expression and post‐translational modification as contributing mechanisms. We hypothesized that endothelial autacoid nitric oxide (NO) would reduce dye coupling human umbilical vein cells (HUVECs). In our subsequent experiments, we sought to isolate specific Cx isoform(s) targeted by NO or NO‐activated...
Myogenic vasoconstriction, an intrinsic response to elevated transmural pressure (TMP), requires the activation of sphingosine kinase (Sk1) and generation reactive oxygen species (ROS). We hypothesized that pressure-induced Sk1 signaling ROS are functionally linked. Using a model cannulated resistance arteries isolated from hamster gracilis muscle, we monitored vessel diameter smooth muscle cell (SMC) Ca2+i (Fura-2) or production (dichlorodihydrofluorescein). Elevation TMP stimulated...
The cystic fibrosis transmembrane conductance regulator (CFTR) attenuates sphingosine-1-phosphate (S1P) signaling in resistance arteries and has emerged as a prominent of myogenic vasoconstriction. This investigation demonstrates that S1P inhibits CFTR activity via adenosine monophosphate-activated kinase (AMPK), establishing potential feedback link. In Baby Hamster Kidney (BHK) cells expressing wild-type human CFTR, (1μmol/L) forskolin-stimulated, CFTR-dependent iodide efflux. S1P's...
In male mice, a circadian rhythm in myogenic reactivity influences the extent of brain injury following subarachnoid haemorrhage (SAH). We hypothesized that female mice have different cerebrovascular phenotype and consequently, distinct SAH-induced phenotype.
Ovarian granulosa cells are coupled via gap junctions containing connexin43 (Cx43 or α-1 connexin). In the absence of Cx43, stop growing in an early preantral stage. However, fact that mature follicles express multiple connexins complicated interpretation this finding. The present experiments were designed to clarify role Cx43 vs. these other earliest stages folliculogenesis. Dye injection revealed from knockout not coupled, and was confirmed by ionic current injections. Furthermore,...
Abstract We have previously shown in cultured rat microvascular endothelial cells (RMEC) that lipopolysaccharide (LPS) stimulates a protein tyrosine kinase (PTK)‐dependent reduction cellular coupling. hypothesized connexin 43 (Cx43) becomes phosphorylated following exposure to LPS. Cx43 was immunoprecipitated from control and LPS‐treated RMEC monolayers. Tyrosine phosphorylation of Cx43, detected by immunoblot, found only the LPS treatment. To verify these results, radiolabeled with [ 32...
Gap junction communication between microvascular endothelial cells has been proposed to contribute the coordination of function. Septic shock may attenuate cell-to-cell communication. We hypothesized that lipopolysaccharide (LPS) attenuates derived from rat hindlimb skeletal muscle. Endothelial grown in monolayers expressed mRNA for connexin 37, 40, and 43. The expression 43 protein was confirmed, but 40 not detected by immunocytochemistry or immunoblot analysis. Intercellular resistance...
Acute β-blockade with metoprolol has been associated increased mortality by undefined mechanisms. Since is a relatively high affinity blocker of β(2)-adrenoreceptors, we hypothesized that some the its use may be due to abrogation β(2)-adrenoreceptor-mediated vasodilation microvessels in different vascular beds. Cardiac output (CO; pressure volume loops), mean arterial (MAP), relative cerebral blood flow (rCBF; laser Doppler), and microvascular brain tissue Po(2) (G2 oxyphor) were measured...