CELLULAR CONTROL MECHANISMS OF CEREBROVASCULAR TONE

Summary

Principal Investigator: David Harder
Abstract: The brain is a highly autoregulated organ in which cerebral blood flow remains relatively constant over a wide range of arterial pressures. Isolated, cannulated cerebral arteries subjected to increasing levels of transmural pressure develop active tone, and constrict as pressure is elevated. Our studies suggest that the vascular endothelium senses pressure increases releasing a transferable vasoactive substance which depolarizes the vascular muscle cell. We will use a bioassay preparation to assess the mechanisms of action of endothelial factors on the electrical and mechanical properties of isolated arterial segments. Isolated cerebral arterial muscle cells will be superfused with the effluent from pressurized cerebral arterial to examine the effect of endothelial factors on whole cell K+ and Ca2+ current measured via patch clamp techniques. Microsomal fractions of arteries loaded with radiolabeled arachidonic acid produce a HPLC fraction which contracts isolated arteries. Production of this fraction and pressure induced activation of cerebral arteries are both blocked by selective inhibition of cytochrome P-450 arachidonic acid metabolism. We will assess the effect of inhibitors of arachidonic acid metabolism with (specific reference to the cytochrome P-450 pathway) on cerebral blood flow measured by laser-Doppler flowmetry through a pial window, and electrical and mechanical responses to pressure in isolated cerebral arteries. We will also assess the effect of this vasoactive HPLC fraction on K+ and Ca2+ currents in isolated muscle cells. To explore the mechanisms by which local metabolic factors override pressure induced activation, the influence of oxygen and oxygen free radicals on electrical and mechanical coupling and endothelial muscle interactions in isolated, pressurized cerebral arteries will be studied. We will also explore the direct effects of reducing PO2 on K+ currents in isolated cerebral arterial muscle cells. to determine the cellular mode of action of a changing pH and PCO2 on cerebral arterial muscle we will examine the effect of changing pH and PCO2 on isolated pressurized cerebral arteries. It is essential to delineate the mechanisms which control normal cerebral blood flow before we can fully understand the etiology of cerebral vascular pathologies such as stroke and impaired cerebral blood flow during ischemia.
Funding Period: 1985-04-01 - 2000-03-31
more information: NIH RePORT

Top Publications

  1. pmc Epoxyeicosatrienoic acid-dependent cerebral vasodilation evoked by metabotropic glutamate receptor activation in vivo
    Xiaoguang Liu
    Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA
    Am J Physiol Heart Circ Physiol 301:H373-81. 2011
  2. pmc Attenuation of neonatal ischemic brain damage using a 20-HETE synthesis inhibitor
    Zeng Jin Yang
    Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
    J Neurochem 121:168-79. 2012
  3. pmc Astrocytes directly influence tumor cell invasion and metastasis in vivo
    Ling Wang
    Department of Pediatrics, Children s Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
    PLoS ONE 8:e80933. 2013
  4. ncbi The effect of superoxide anion on autoregulation of cerebral blood flow
    Drazen Zagorac
    Cardiovascular Research Center, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Stroke 36:2589-94. 2005
  5. ncbi Endothelial dysfunction and hypertension in rats transduced with CYP4A2 adenovirus
    David R Harder
    Circ Res 98:866-7. 2006
  6. ncbi Ceramide elevates 12-hydroxyeicosatetraenoic acid levels and upregulates 12-lipoxygenase in rat primary hippocampal cell cultures containing predominantly astrocytes
    Vidudala V T S Prasad
    Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Neurochem Int 53:220-9. 2008
  7. pmc Adenosine can mediate its actions through generation of reactive oxygen species
    Debebe Gebremedhin
    Department of Physiology, Medical College of Wisconsin, Milwaukee, 53226, USA
    J Cereb Blood Flow Metab 30:1777-90. 2010

Scientific Experts

  • David R Harder
  • Richard J Roman
  • Debebe Gebremedhin
  • Ling Wang
  • Zeng Jin Yang
  • Raymond C Koehler
  • Xiaoguang Liu
  • Vidudala V T S Prasad
  • Drazen Zagorac
  • Kevin R Rarick
  • Ramani Ramchandran
  • Jill Gershan
  • Michael B Dwinell
  • Stephanie M Cossette
  • Kathleen K Kibler
  • Daina A Crafa
  • Herman Kwansa
  • Lee J Martin
  • Erin L Carter
  • Sung Hee Hwang
  • Bruce D Hammock
  • Chunyuan Li
  • John R Falck
  • David Lourim
  • Brian Weinberger
  • Kassem Nithipatikom
  • Cindy Zhang
  • Ken Yamaura

Detail Information

Publications7

  1. pmc Epoxyeicosatrienoic acid-dependent cerebral vasodilation evoked by metabotropic glutamate receptor activation in vivo
    Xiaoguang Liu
    Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA
    Am J Physiol Heart Circ Physiol 301:H373-81. 2011
    ..Epoxide hydrolase activity and 20-HETE synthesis limit the duration of the response to prolonged mGluR activation...
  2. pmc Attenuation of neonatal ischemic brain damage using a 20-HETE synthesis inhibitor
    Zeng Jin Yang
    Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
    J Neurochem 121:168-79. 2012
    ..Thus, 20-HETE can exert direct effects on key proteins involved in neuronal excitotoxicity in vivo and contributes to neurodegeneration after global cerebral ischemia in immature brain...
  3. pmc Astrocytes directly influence tumor cell invasion and metastasis in vivo
    Ling Wang
    Department of Pediatrics, Children s Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
    PLoS ONE 8:e80933. 2013
    ..Collectively, our data implicate astrocyte-derived MMP-2 and MMP-9 as critical players that facilitate tumor cell migration and invasion leading to brain metastasis. ..
  4. ncbi The effect of superoxide anion on autoregulation of cerebral blood flow
    Drazen Zagorac
    Cardiovascular Research Center, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Stroke 36:2589-94. 2005
    ..Given that the levels of superoxide anion (O2*-) are increased in these conditions, we postulate that O2*- contributes to the impairment of CBF autoregulation...
  5. ncbi Endothelial dysfunction and hypertension in rats transduced with CYP4A2 adenovirus
    David R Harder
    Circ Res 98:866-7. 2006
  6. ncbi Ceramide elevates 12-hydroxyeicosatetraenoic acid levels and upregulates 12-lipoxygenase in rat primary hippocampal cell cultures containing predominantly astrocytes
    Vidudala V T S Prasad
    Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Neurochem Int 53:220-9. 2008
    ..Induction of 12-LOX pathway by ceramide may have implications in understanding pathophysiology of neurodegenerative diseases involving ROS generation and inflammation...
  7. pmc Adenosine can mediate its actions through generation of reactive oxygen species
    Debebe Gebremedhin
    Department of Physiology, Medical College of Wisconsin, Milwaukee, 53226, USA
    J Cereb Blood Flow Metab 30:1777-90. 2010
    ..This signaling pathway could be one of the mediators of the cerebral vasodilatory actions of adenosine...