CONTROL OF NEONATAL CIRCULATION

Summary

Principal Investigator: Charles W Leffler
Abstract: DESCRIPTION (provided by applicant): Investigation of mechanisms involved in perinatal asphyxia-induced cerebrovascular dysfunction is important because fetal and neonatal asphyxia can cause of perinatal brain damage and failure of blood flow regulation is a critical component. Carbon monoxide (CO) from astrocyte heme oxygenase (HO) is important in regulation of newborn cerebral circulation and preliminary data suggest HO products can provide cerebrovascular and astrocytic protection from asphyxia-induced damage. The research proposed pursues the unifying hypothesis that, in newborn brain, asphyxia disrupts astrocyte CO signaling and cerebral arteriolar smooth muscle (VSM) Ca2+ signaling and/or BKCa channel activity causing cerebrovascular dysfunction, while elevation of cytoprotective CO and bilirubin limit the dysfunction. To test this hypothesis, four specific hypotheses will be tested using a novel asphyxia model in newborn pigs: 1. Asphyxia injures astrocytes causing loss of CO-mediated dilation of pial arterioles, 2. Asphyxia depresses cerebral VSM CO-induced Ca2+ sparks, BKCa channel activity, and dilation, 3. Reactive oxygen species (ROS) are major contributors to asphyxia-induced astrocyte and VSM injury, and 4. Cytoprotective CO and bilirubin reduce asphyxia-induced ROS and post-asphyxia astrocyte and VSM dysfunction. Techniques will be used that allow investigation of intact newborn cerebral microcirculation in vivo, isolated pressurized cerebral arterioles, and freshly isolated astrocytes, microvessels and smooth muscle cells. Such research is unique by studying intact cerebral circulation, production of CO by intact brain and isolated astrocytes and microvessels, and investigating, at the cellular level, mechanisms responsible cerebral vascular dysfunction. In addition, experimental interventions that may attenuate cerebrovascular malfunction caused by asphyxia are examined. Cranial windows allow observation of microcirculation, collection of cortical CSF and topical application of agonists, precursors and inhibitors. CO production in vivo and in vitro is identified and quantified by gas chromatography-mass spectrometry. Astrocytes, cerebral arterioles, and cerebral arteriole smooth muscle cells isolated from control and post-asphyxia brains allow study of ROS, CO production, arteriolar reactivity, and vascular smooth muscle function. Global cytosolic Ca2+ and Ca2+ sparks in brain slices, intact arterioles and VSM 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 BKCa channel activity. These studies are important because disorders of the cerebral circulation in the newborn period are major causes of sickness and death and can result in lifelong disabilities in survivors.
Funding Period: 1985-04-01 - 2017-05-31
more information: NIH RePORT

Top Publications

  1. pmc Cyclooxygenase products stimulate carbon monoxide production by piglet cerebral microvessels
    Alie Kanu
    Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    Exp Biol Med (Maywood) 231:181-5. 2006
  2. pmc Model-derived assessment of cerebrovascular resistance and cerebral blood flow following traumatic brain injury
    Michael L Daley
    Department of Electrical and Computer Engineering, The University of Memphis, Engineering Science Building, Memphis, TN 38152 3180, USA
    Exp Biol Med (Maywood) 235:539-45. 2010
  3. pmc Time-dependent action of carbon monoxide on the newborn cerebrovascular circulation
    Kenneth R Knecht
    Department of Physiology, University of Tennessee Health Science Center, 894 Union Ave, Memphis, TN 38163, USA
    Am J Physiol Heart Circ Physiol 299:H70-5. 2010
  4. pmc Nox4 NADPH oxidase-derived reactive oxygen species, via endogenous carbon monoxide, promote survival of brain endothelial cells during TNF-α-induced apoptosis
    Shyamali Basuroy
    Dept of Physiology, University of Tennessee Health Science Center, 894 Union Ave, Memphis, TN 38163, USA
    Am J Physiol Cell Physiol 300:C256-65. 2011
  5. pmc Distinct effects of intravascular and extravascular angiotensin II on cerebrovascular circulation of newborn pigs
    Kenneth R Knecht
    Department of Pediatrics, University of Tennessee Center for the Health Sciences, Memphis, TN 38163, USA
    Exp Biol Med (Maywood) 235:1479-88. 2010
  6. pmc Hydrogen sulfide and cerebral microvascular tone in newborn pigs
    Charles W Leffler
    Laboratory for Research in Neonatal Physiology, Department of Physiology, University of Tennessee Health Science Center, 894 Union Ave, Memphis, TN 38163, USA
    Am J Physiol Heart Circ Physiol 300:H440-7. 2011
  7. pmc Hydrogen sulfide dilates cerebral arterioles by activating smooth muscle cell plasma membrane KATP channels
    Guo Hua Liang
    Dept of Physiology, Univ of Tennessee Health Science Ctr, Memphis, TN 38163, USA
    Am J Physiol Heart Circ Physiol 300:H2088-95. 2011
  8. pmc Glutamate-induced calcium signals stimulate CO production in piglet astrocytes
    Qi Xi
    Laboratory for Research in Neonatal Physiology, Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
    Am J Physiol Heart Circ Physiol 301:H428-33. 2011
  9. pmc Functional role of astrocyte glutamate receptors and carbon monoxide in cerebral vasodilation response to glutamate
    Helena Parfenova
    Department of Physiology, University of Tennessee Health Science Center, Memphis, 38163, USA
    Am J Physiol Heart Circ Physiol 302:H2257-66. 2012
  10. pmc Hydrogen sulfide activates Ca²⁺ sparks to induce cerebral arteriole dilatation
    Guo Hua Liang
    Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    J Physiol 590:2709-20. 2012

Research Grants

Detail Information

Publications24

  1. pmc Cyclooxygenase products stimulate carbon monoxide production by piglet cerebral microvessels
    Alie Kanu
    Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    Exp Biol Med (Maywood) 231:181-5. 2006
    ..Conversely, Cox activity is not affected by HO-catalyzed heme metabolites. These data suggest that some cerebrovascular functions attributable to Cox activity could be mediated by CO...
  2. pmc Model-derived assessment of cerebrovascular resistance and cerebral blood flow following traumatic brain injury
    Michael L Daley
    Department of Electrical and Computer Engineering, The University of Memphis, Engineering Science Building, Memphis, TN 38152 3180, USA
    Exp Biol Med (Maywood) 235:539-45. 2010
    ..96 (P < 0.01) and r = 0.97 (P <or= 0.01), respectively. The assessment of model-derived cerebrovascular resistance and CBF with changes of CPP provides a means to monitor continuously the state of cerebrovascular regulation...
  3. pmc Time-dependent action of carbon monoxide on the newborn cerebrovascular circulation
    Kenneth R Knecht
    Department of Physiology, University of Tennessee Health Science Center, 894 Union Ave, Memphis, TN 38163, USA
    Am J Physiol Heart Circ Physiol 299:H70-5. 2010
    ..The interaction between heme oxygenase/CO and NOS/NO could form a negative feedback system in the control of cerebral vascular tone...
  4. pmc Nox4 NADPH oxidase-derived reactive oxygen species, via endogenous carbon monoxide, promote survival of brain endothelial cells during TNF-α-induced apoptosis
    Shyamali Basuroy
    Dept of Physiology, University of Tennessee Health Science Center, 894 Union Ave, Memphis, TN 38163, USA
    Am J Physiol Cell Physiol 300:C256-65. 2011
    ..The ability of CO to inhibit TNF-α-induced ERK1/2 and p38 MAPK activities in an Akt-dependent manner appears to be the key element in ROS-dependent survival of endothelial cells during TNF-α-mediated brain inflammatory disease...
  5. pmc Distinct effects of intravascular and extravascular angiotensin II on cerebrovascular circulation of newborn pigs
    Kenneth R Knecht
    Department of Pediatrics, University of Tennessee Center for the Health Sciences, Memphis, TN 38163, USA
    Exp Biol Med (Maywood) 235:1479-88. 2010
    ..Clinical manipulation of the renin-angiotensin system will have disparate actions on cerebral circulation depending on the functional integrity of the intima and ACE...
  6. pmc Hydrogen sulfide and cerebral microvascular tone in newborn pigs
    Charles W Leffler
    Laboratory for Research in Neonatal Physiology, Department of Physiology, University of Tennessee Health Science Center, 894 Union Ave, Memphis, TN 38163, USA
    Am J Physiol Heart Circ Physiol 300:H440-7. 2011
    ..These data show that H2S is a dilator of the newborn cerebral circulation and that endogenous CSE can produce sufficient H2S to decrease vascular tone. H2S appears to be a physiologically significant dilator in the cerebral circulation...
  7. pmc Hydrogen sulfide dilates cerebral arterioles by activating smooth muscle cell plasma membrane KATP channels
    Guo Hua Liang
    Dept of Physiology, Univ of Tennessee Health Science Ctr, Memphis, TN 38163, USA
    Am J Physiol Heart Circ Physiol 300:H2088-95. 2011
    ..These data indicate that smooth muscle cell K(ATP) currents control newborn cerebral arteriole contractility and that H(2)S dilates cerebral arterioles by activating smooth muscle cell K(ATP) channels containing SUR2 subunits...
  8. pmc Glutamate-induced calcium signals stimulate CO production in piglet astrocytes
    Qi Xi
    Laboratory for Research in Neonatal Physiology, Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
    Am J Physiol Heart Circ Physiol 301:H428-33. 2011
    ..Taken together, our data are consistent with the hypothesis that glutamate elevates [Ca(2+)](i) in astrocytes, leading to Ca(2+)- and calmodulin-dependent HO-2 activation, and CO production...
  9. pmc Functional role of astrocyte glutamate receptors and carbon monoxide in cerebral vasodilation response to glutamate
    Helena Parfenova
    Department of Physiology, University of Tennessee Health Science Center, Memphis, 38163, USA
    Am J Physiol Heart Circ Physiol 302:H2257-66. 2012
    ....
  10. pmc Hydrogen sulfide activates Ca²⁺ sparks to induce cerebral arteriole dilatation
    Guo Hua Liang
    Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    J Physiol 590:2709-20. 2012
    ..The subsequent elevation in transient KCa current frequency leads to membrane hyperpolarization, a reduction in global [Ca²⁺]i and vasodilatation...
  11. pmc Cerebrovascular dilation via selective targeting of the cholane steroid-recognition site in the BK channel β1-subunit by a novel nonsteroidal agent
    Anna N Bukiya
    Departments of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    Mol Pharmacol 83:1030-44. 2013
    ..In conclusion, we have identified for the first time a nonsteroidal agent that selectively activates β1-containing BK channels by targeting the steroid-sensing site in BK β1, rendering vasodilation...
  12. pmc Glutamate regulates Ca2+ signals in smooth muscle cells of newborn piglet brain slice arterioles through astrocyte- and heme oxygenase-dependent mechanisms
    Qi Xi
    Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
    Am J Physiol Heart Circ Physiol 298:H562-9. 2010
    ..These data also indicate that soluble guanylyl cyclase is involved in CO activation of Ca(2+) sparks in arteriole smooth muscle cells...
  13. pmc Stroke with subarachnoid hemorrhage: assessment of cerebrovascular pressure regulation and simulated cerebrovascular resistance
    Michael L Daley
    Department of Electrical and Computer Engineering, The University of Memphis, Engineering Science Building, Rm 208B, Memphis, TN 38152 3180, USA
    Acta Neurochir Suppl 102:321-5. 2008
    ..The aim of this study was to assess changes of cerebrovascular regulation and CVR by evaluating changes of cerebrovascular pressure transmission in patients with SAH...
  14. pmc Carbon monoxide and hydrogen sulfide: gaseous messengers in cerebrovascular circulation
    Charles W Leffler
    Dept of Physiology, University of Tennessee Health Science Center, 894 Union Ave, Memphis, TN 38163, USA
    J Appl Physiol (1985) 100:1065-76. 2006
    ..Both the HO-CO and CSE-H2S systems have potential to interact with NO and prostanoids in the cerebral circulation. Much of the physiology and biochemistry of HO-CO and CSE-H2S in the cerebral circulation remains open for exploration...
  15. pmc KCa channel insensitivity to Ca2+ sparks underlies fractional uncoupling in newborn cerebral artery smooth muscle cells
    Anlong Li
    Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    Am J Physiol Heart Circ Physiol 291:H1118-25. 2006
    ..Overall, KCa channel insensitivity to Ca2+ sparks is a prominent factor underlying fractional Ca2+ spark uncoupling in newborn cerebral artery myocytes...
  16. pmc Carbon monoxide contributes to hypotension-induced cerebrovascular vasodilation in piglets
    Alie Kanu
    Dept of Physiology, Univ of Tennessee Health Science Center, 894 Union Ave, Memphis, TN 38163, USA
    Am J Physiol Heart Circ Physiol 291:H2409-14. 2006
    ..These data suggest that endogenously produced CO contributes to cerebrovascular dilation in response to reduced perfusion pressure...
  17. pmc Contributions of astrocytes and CO to pial arteriolar dilation to glutamate in newborn pigs
    Charles W Leffler
    Dept of Physiology, University of Tennessee, Memphis, TN 38163, USA
    Am J Physiol Heart Circ Physiol 291:H2897-904. 2006
    ..The concurrent loss of CO production and pial arteriolar dilation to glutamate following astrocyte injury suggests astrocytes may employ CO as a gasotransmitter for glutamatergic cerebrovascular dilation...
  18. pmc Carbon monoxide and Ca2+-activated K+ channels in cerebral arteriolar responses to glutamate and hypoxia in newborn pigs
    Alie Kanu
    Laboratory for Resaerch in Neonatal Physiology, Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, USA
    Am J Physiol Heart Circ Physiol 293:H3193-200. 2007
    ....
  19. pmc Age and species dependence of pial arteriolar responses to topical carbon monoxide in vivo
    David C Holt
    Laboratory for Research in Neonatal Physiology, Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
    Exp Biol Med (Maywood) 232:1465-9. 2007
    ..In conclusion, rat pial arterioles like those in piglets dilate to CO in vivo, but there are age and species differences with regard to reactivity and interaction with NO...
  20. pmc Influence of hypercapnic vasodilation on cerebrovascular autoregulation and pial arteriolar bed resistance in piglets
    Nithya Narayanan
    Department of Electrical and Computer Engineering, The University of Memphis, Engineering Science Bldg, Rm 208B, Memphis, TN 38152 3180, USA
    J Appl Physiol (1985) 105:152-7. 2008
    ..Our physiologically based biomechanical model of cerebrovascular pressure transmission accurately estimates the changes in arteriolar resistance during conditions of active and passive cerebrovascular reactivity...
  21. pmc Assessment of cerebrovascular resistance with a model of cerebrovascular pressure transmission
    Nithya Narayanan
    Department of Electrical and Computer Engineering, The University of Memphis, Memphis, TN 38152 6574, United States
    Med Eng Phys 31:254-60. 2009
    ....
  22. pmc Roles of glia limitans astrocytes and carbon monoxide in adenosine diphosphate-induced pial arteriolar dilation in newborn pigs
    Alie Kanu
    Laboratory for Research in Neonatal Physiology, Department of Physiology, University of Tennessee Health Science Center, Memphis, Tenn, USA
    Stroke 40:930-5. 2009
    ..We hypothesize ADP stimulates CO production by glia limitans astrocytes and that this CO causes pial arteriolar dilation...
  23. pmc Assessment of cerebrovascular resistance with model of cerebrovascular pressure transmission
    Nithya Narayanan
    Department of Electrical and Computer Engineering, The University of Memphis, Engineering Science Building, Rm 209A, Memphis, TN 38152 3180, USA
    Acta Neurochir Suppl 102:37-41. 2008
    ....
  24. pmc CORM-A1 prevents blood-brain barrier dysfunction caused by ionotropic glutamate receptor-mediated endothelial oxidative stress and apoptosis
    Shyamali Basuroy
    Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    Am J Physiol Cell Physiol 304:C1105-15. 2013
    ..Antioxidant CORMs therapy may help preserve BBB functional integrity in neonatal cerebrovascular disease...

Research Grants30

  1. Modification of Vascular Signaling in the Brain by ROS
    DAVID RAE HARDER; Fiscal Year: 2013
    ..We hope Dr. Daniel;Beard has agreed to act as our consultant and use data obtained in this project to guide future basic and clinical investigations into models of cerebral blood flow regulation. ..
  2. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  3. Cerebrovascular Stress and Circulating Endothelial Cells
    Helena Parfenova; Fiscal Year: 2013
    ....
  4. Prevention and management of perioperative pulmonary embolism
    Vladimir R Muzykantov; Fiscal Year: 2013
    ....
  5. CHRONIC INTERMITTENT HYPOXIA, NEUROVASCULAR DYSFUNCTION AND STROKE
    Costantino Iadecola; Fiscal Year: 2013
    ..Ultimately, the results of the proposed studies may suggest novel mechanism-based approaches to prevent or treat the deleterious effects of this highly prevalent condition. ..
  6. Carbon monoxide and vascular cell function
    William Durante; Fiscal Year: 2013
    ..This project will explore the possible therapeutic application of low doses of carbon monoxide in preventing the blockage of arteries and in treating high blood pressure. ..