Carbon monoxide (CO) is produced by catabolism of heme via heme oxygenase (HO). CO dilates cerebral arterioles by activating Ca activated K (Kca) channels. The constitutive HO isoform, HO-2, is highly expressed in astrocytes that coat cerebral arterioles and have glutamate receptors. This is important because CO is a mediator of newborn cerebral vasodilatation in response to glutamatergic neuronal activity. Although microvascular cells can produce CO, the physiological origin of CO that regulates cerebral vascular tone is unknown. The proposed research will pursue the hypothesis that perivascular astrocytes HO-2 makes CO to control newborn cerebrovascular circulation during glutamatergic stimulation.
Three specific aims will be addressed: 1. Compare, in vivo, contributions of astrocytes, neurons, and endothelium to cerebral CO production and pial arteriolar dilation in response to glutamate, 2. Determine, in vitro, causal relationships among glutamate, cystolic Ca transients, global Ca, and astrocytes production of CO, 3. Investigate the ability of CO produced by astrocytes to activate vascular smooth muscle KCa channels. Techniques allowing investigation of intact cerebral microcirculation, intact neurovascular units in brain slices, freshly isolated astrocytes, astrocytes in primary culture, and freshly isolated cerebral arteriolar myocytes alone and in combination with astrocytes will be employed. Such research is unique by studying intact cerebral circulation and investigating, at the cellular level, the mechanisms regulating astrocytes production of a gasotransmitter, and how such astrocytes production can affect adjacent vascular smooth muscle to alter vascular tone. Cranial windows allow investigation of intact cerebral circulation, monitoring of brain surface CO production, and topical application of agonists and inhibitors. Freshly isolated astrocytes and astrocytes grown on microcarrier beads allow study of the mechanisms involved in glutamate stimulation of CO production. Global cystolic Ca and Ca transients in brain slices, astrocytes, cerebrovascular myocytes, and reunited astrocytes and myocytes will be studied using fluorescent indicator technology with a dual excitation, single emission system and laser scanning confocal microscopy, respectively. Patch clamp techniques will be used to examine KCa channel activity. Cerebral circulatory disorders in newborns are major causes of morbidity and mortality and can result in life long disabilities. Control of cerebrovascular circulation is impaired by pathological conditions. Better understanding of mechanisms of cerebromicrovascular humoral communication is needed.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL034059-26
Application #
7795044
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Reid, Diane M
Project Start
1985-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
26
Fiscal Year
2010
Total Cost
$365,000
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Physiology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Liu, Jianxiong; Pourcyrous, Massroor; Fedinec, Alex L et al. (2017) Preventing harmful effects of epileptic seizures on cerebrovascular functions in newborn pigs: does sex matter? Pediatr Res 82:881-887
Harsono, Mimily; Pourcyrous, Massroor; Jolly, Elliott J et al. (2016) Selective head cooling during neonatal seizures prevents postictal cerebral vascular dysfunction without reducing epileptiform activity. Am J Physiol Heart Circ Physiol 311:H1202-H1213
Chang, Jennifer; Fedinec, Alexander L; Kuntamallappanavar, Guruprasad et al. (2016) Endothelial Nitric Oxide Mediates Caffeine Antagonism of Alcohol-Induced Cerebral Artery Constriction. J Pharmacol Exp Ther 356:106-15
Liu, Jianxiong; Fedinec, Alexander L; Leffler, Charles W et al. (2015) Enteral supplements of a carbon monoxide donor CORM-A1 protect against cerebrovascular dysfunction caused by neonatal seizures. J Cereb Blood Flow Metab 35:193-9
Pourcyrous, Massroor; Basuroy, Shyamali; Tcheranova, Dilyara et al. (2015) Brain-derived circulating endothelial cells in peripheral blood of newborn infants with seizures: a potential biomarker for cerebrovascular injury. Physiol Rep 3:
Nnorom, Chukwuma C; Davis, Corinne; Fedinec, Alexander L et al. (2014) Contributions of KATP and KCa channels to cerebral arteriolar dilation to hypercapnia in neonatal brain. Physiol Rep 2:
Bukiya, Anna; Dopico, Alejandro M; Leffler, Charles W et al. (2014) Dietary cholesterol protects against alcohol-induced cerebral artery constriction. Alcohol Clin Exp Res 38:1216-26
Basuroy, Shyamali; Leffler, Charles W; Parfenova, Helena (2013) CORM-A1 prevents blood-brain barrier dysfunction caused by ionotropic glutamate receptor-mediated endothelial oxidative stress and apoptosis. Am J Physiol Cell Physiol 304:C1105-15
Bukiya, Anna N; McMillan, Jacob E; Fedinec, Alexander L et al. (2013) Cerebrovascular dilation via selective targeting of the cholane steroid-recognition site in the BK channel ?1-subunit by a novel nonsteroidal agent. Mol Pharmacol 83:1030-44
Liang, Guo Hua; Xi, Qi; Leffler, Charles W et al. (2012) Hydrogen sulfide activates Ca²? sparks to induce cerebral arteriole dilatation. J Physiol 590:2709-20

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