HS mediates the vasodilator effect of endothelin-1 in the cerebral circulation.

HS is an endogenous gasotransmitter that increases cerebral blood flow. In the cerebral vascular endothelium, HS is produced by cystathionine δ-lyase (CSE). Endothelin-1 (ET-1) has constrictor and dilator influences on the cerebral circulation.

Astrocyte-produced carbon monoxide and the carbon monoxide donor CORM-A1 protect against cerebrovascular dysfunction caused by prolonged neonatal asphyxia.

Neonatal asphyxia leads to cerebrovascular disease and neurological complications via a mechanism that may involve oxidative stress. Carbon monoxide (CO) is an antioxidant messenger produced via a heme oxygenase (HO)-catalyzed reaction. Cortical astrocytes are the major cells in the brain that express constitutive HO-2 isoform.

Does prolonged severe hypercapnia interfere with normal cerebrovascular function in piglets?

Background: Hypercapnia causes cerebral vasodilation and increased cerebral blood flow (CBF). During prolonged hypercapnia it is unknown whether cerebral vasodilation persists and whether cerebrovascular function is preserved. We investigated the effects of prolonged severe hypercapnia on pial arteriolar diameters (PAD) and cerebrovascular reactivity to vasodilators and vasoconstrictors.

Preventing harmful effects of epileptic seizures on cerebrovascular functions in newborn pigs: does sex matter?

BackgroundThe potential contribution of sex-related variables to cerebrovascular functions in neonates remains elusive. Newborn piglets provide a translationally relevant model for studying the effects of seizures in the neonatal brain. The present study investigated whether sex differences contribute to cerebrovascular functions in healthy and epileptic newborn pigs.

Endothelial Nitric Oxide Mediates Caffeine Antagonism of Alcohol-Induced Cerebral Artery Constriction.

Despite preventive education, the combined consumption of alcohol and caffeine (particularly from "energy drinks") continues to rise. Physiologic perturbations by separate intake of ethanol and caffeine have been widely documented. However, the biologic actions of the alcohol-caffeine combination and their underlying subcellular mechanisms have been scarcely studied.

Brain-derived circulating endothelial cells in peripheral blood of newborn infants with seizures: a potential biomarker for cerebrovascular injury.

Neonatal seizures have been associated with cerebrovascular endothelial injury and neurological disabilities. In a piglet model, the long-term loss of endothelial regulation of cerebral blood flow coincides with the surge of brain-derived circulating endothelial cells (BCECs) in blood. We hypothesized that BCECs could serve as a noninvasive biomarker of cerebrovascular injury in neonates with seizures.

Enteral supplements of a carbon monoxide donor CORM-A1 protect against cerebrovascular dysfunction caused by neonatal seizures.

Cerebral blood flow dysregulation caused by oxidative stress contributes to adverse neurologic outcome of seizures. A carbon monoxide (CO) donor CORM-A1 has antioxidant and cytoprotective properties. We investigated whether enteral supplements of CORM-A1 can improve cerebrovascular outcome of bicuculline-induced seizures in newborn piglets.

Contributions of KATP and KCa channels to cerebral arteriolar dilation to hypercapnia in neonatal brain.

Mechanisms by which Pco2 controls cerebral vascular tone remain uncertain. We hypothesize that potassium channel activation contributes to the neonatal cerebrovascular dilation in response to increases in Paco2. To test this hypothesis, experiments were performed on newborn pigs with surgically implanted, closed cranial windows.

Dietary cholesterol protects against alcohol-induced cerebral artery constriction.

Background: Binge drinking represents the major form of excessive alcohol (ethanol [EtOH]) consumption in the United States. Episodic (such as binge) drinking results in blood alcohol levels (BAL) of 18 to 80 mM and leads to alcohol-induced cerebral artery constriction (AICAC). AICAC was shown to arise from EtOH-induced inhibition of large-conductance, calcium/voltage-gated potassium (BK) channels in the vascular smooth muscle.

CORM-A1 prevents blood-brain barrier dysfunction caused by ionotropic glutamate receptor-mediated endothelial oxidative stress and apoptosis.

In cerebral microvascular endothelial cells (CMVEC) of newborn pigs, glutamate at excitotoxic concentrations (mM) causes apoptosis mediated by reactive oxygen species (ROS). Carbon monoxide (CO) produced by CMVEC or delivered by a CO-releasing molecule, CORM-A1, has antioxidant properties. We tested the hypothesis that CORM-A1 prevents cerebrovascular endothelial barrier dysfunction caused by glutamate excitotoxicity.

Cerebrovascular dilation via selective targeting of the cholane steroid-recognition site in the BK channel β1-subunit by a novel nonsteroidal agent.

The Ca(2+)/voltage-gated K(+) large conductance (BK) channel β1 subunit is particularly abundant in vascular smooth muscle. By determining their phenotype, BK β1 allows the BK channels to reduce myogenic tone, facilitating vasodilation. The endogenous steroid lithocholic acid (LCA) dilates cerebral arteries via BK channel activation, which requires recognition by a BK β1 site that includes Thr169.

Hydrogen sulfide activates Ca²⁺ sparks to induce cerebral arteriole dilatation.

Hydrogen sulfide (H₂S) is a gaseous vasodilator produced by endothelial cells. Mechanisms by which H₂S induces vasodilatation are unclear. We tested the hypothesis that H₂S dilates cerebral arterioles by modulating local and global intracellular Ca²⁺ signals in smooth muscle cells.

Functional role of astrocyte glutamate receptors and carbon monoxide in cerebral vasodilation response to glutamate.

In newborn pigs, vasodilation of pial arterioles in response to glutamate is mediated via carbon monoxide (CO), a gaseous messenger endogenously produced from heme degradation by a heme oxygenase (HO)-catalyzed reaction. We addressed the hypothesis that ionotropic glutamate receptors (iGluRs), including N-methyl-D-aspartic acid (NMDA)- and 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA)/kainate-type receptors, expressed in cortical astrocytes mediate glutamate-induced astrocyte HO activation that leads to cerebral vasodilation. Acute vasoactive effects of topical iGluR agonists were determined by intravital microscopy using closed cranial windows in anesthetized newborn pigs.

Antioxidant roles of heme oxygenase, carbon monoxide, and bilirubin in cerebral circulation during seizures.

Postictal cerebrovascular dysfunction is an adverse effect of seizures in newborn piglets. The brain heme oxygenase (HO) provides protection against cerebrovascular dysfunction. We investigated the contribution of reactive oxygen species (ROS) to seizure-induced vascular damage and the mechanism of HO vasoprotection.

Arachidonic acid- and prostaglandin E2-induced cerebral vasodilation is mediated by carbon monoxide, independent of reactive oxygen species in piglets.

Arachidonic acid (AA) and prostaglandin (PG) E(2) stimulate carbon monoxide (CO) production, and AA metabolism is known to be associated with the generation of reactive oxygen species (ROS). This study was conducted to address the hypothesis that CO and/or ROS mediate cerebrovascular dilation in newborn pigs. Experiments were performed on anesthetized newborn pigs with closed cranial windows.

Glutamate-induced calcium signals stimulate CO production in piglet astrocytes.

Glutamate-stimulated, astrocyte-derived carbon monoxide (CO) causes cerebral arteriole dilation by activating smooth muscle cell large-conductance Ca(2+)-activated K(+) channels. Here, we examined the hypothesis that glutamate activates heme oxygenase (HO)-2 and CO production via the intracellular Ca(2+) concentration ([Ca(2+)](i))/Ca(2+)-calmodulin signaling pathway in newborn pig astrocytes. The major findings are: 1) glutamate stimulated Ca(2+) transients and increased steady-state [Ca(2+)](i) in cerebral cortical astrocytes in primary culture, 2) in astrocytes permeabilized with ionomycin, elevation of [Ca(2+)](i) concentration-dependently increased CO production, 3) glutamate did not affect CO production at any [Ca(2+)](i) when the [Ca(2+)](i) was held constant, 4) thapsigargin, a sarco/endoplasmic reticulum Ca(2+)-ATPase blocker, decreased basal CO production and blocked glutamate-induced increases in CO, and 5) calmidazolium, a calmodulin inhibitor, blocked CO production induced by glutamate and by [Ca(2+)](i) elevation.

Carbon monoxide as an endogenous vascular modulator.

Carbon monoxide (CO) is produced by heme oxygenase (HO)-catalyzed heme degradation to CO, iron, and biliverdin. HO has two active isoforms, HO-1 (inducible) and HO-2 (constitutive). HO-2, but not HO-1, is highly expressed in endothelial and smooth muscle cells and in adjacent astrocytes in the brain.

Hydrogen sulfide dilates cerebral arterioles by activating smooth muscle cell plasma membrane KATP channels.

Hydrogen sulfide (H(2)S) is a gaseous signaling molecule that appears to contribute to the regulation of vascular tone and blood pressure. Multiple potential mechanisms of vascular regulation by H(2)S exist. Here, we tested the hypothesis that piglet cerebral arteriole smooth muscle cells generate ATP-sensitive K(+) (K(ATP)) currents and that H(2)S induces vasodilation by activating K(ATP) currents.

Hydrogen sulfide and cerebral microvascular tone in newborn pigs.

Hydrogen sulfide (H2S) is a gaseous signaling molecule that appears to be involved in numerous biological processes, including regulation of blood pressure and vascular tone. The present study is designed to address the hypothesis that H2S is a functionally significant, endogenous dilator in the newborn cerebrovascular circulation. In vivo experiments were conducted using newborn pigs with surgically implanted, closed, cranial windows.

Distinct effects of intravascular and extravascular angiotensin II on cerebrovascular circulation of newborn pigs.

Angiotensin II (AngII) is important in regulation of vascular resistance and control of blood flow among organs and tissues. The effect of AngII on the cerebral microvasculature may be mediated or altered by endothelial-derived signals. The aim of this study was to test the hypothesis that blood AngII dilates neonatal pial arterioles via an endothelial-dependent mechanism but brain AngII can constrict pial arterioles by activating smooth muscle AT1 receptors.

Nox4 NADPH oxidase-derived reactive oxygen species, via endogenous carbon monoxide, promote survival of brain endothelial cells during TNF-α-induced apoptosis.

We investigated the role of reactive oxygen species (ROS) in promoting cell survival during oxidative stress induced by the inflammatory mediator tumor necrosis factor-α (TNF-α) in cerebral microvascular endothelial cells (CMVEC) from newborn piglets. Nox4 is the major isoform of NADPH oxidase responsible for TNF-α-induced oxidative stress and apoptosis in CMVEC. We present novel data that Nox4 NADPH oxidase-derived ROS also initiate a cell survival mechanism by increasing production of a gaseous antioxidant mediator carbon monoxide (CO) by constitutive heme oxygenase-2 (HO-2).

Time-dependent action of carbon monoxide on the newborn cerebrovascular circulation.

Carbon monoxide (CO) causes cerebral arteriolar dilation in newborn pigs by the activation of large-conductance Ca(2+)-activated K(+) channels. In adult rat cerebral and skeletal muscle arterioles, CO has been reported to produce constriction caused by the inhibition of nitric oxide (NO) synthase (NOS). We hypothesized that, in contrast to dilation to acute CO, more prolonged exposure of newborn cerebral arterioles to elevated CO produces constriction by reducing NO.

Model-derived assessment of cerebrovascular resistance and cerebral blood flow following traumatic brain injury.

The published guidelines point out the need for the development of methods that individualize patient cerebral perfusion management and minimize secondary ischemic complications associated with traumatic brain injury. A laboratory method has been developed to determine model-derived assessments of cerebrovascular resistance (mCVR) and cerebral blood flow (mCBF) from cerebrovascular pressure transmission, and the dynamic relationship between arterial blood pressure (ABP) and intracranial pressure (ICP). The aim of this two-fold study is to (1) evaluate relative changes in the model-derived parameters of mCVR and mCBF with the corresponding changes in the pial arteriolar vascular parameters of pial arteriolar resistance (PAR) and relative pial arteriolar blood flow (rPABF); and (2) examine the efficacy of the proposed modeling methodology for continuous assessment of the state of cerebrovascular regulation by evaluating relative changes in the model-derived parameters of CBF and cerebrovascular resistance in relation to changes of cerebral perfusion pressure prior to and following fluid percussion brain injury.

Epileptic seizures increase circulating endothelial cells in peripheral blood as early indicators of cerebral vascular damage.

Circulating endothelial cells (CECs) are nonhematopoetic mononuclear cells in peripheral blood that are dislodged from injured vessels during cardiovascular disease, systemic vascular disease, and inflammation. Their occurrence during cerebrovascular insults has not been previously described. Epileptic seizures cause the long-term loss of cerebrovascular endothelial dilator function.