Flow-Mediated Dilation of Human Coronary Arterioles

Summary

Principal Investigator: David D Gutterman
Affiliation: Medical College of Wisconsin
Country: USA
Abstract: Shear stress acting on endothelial cells produces vasodilation. This is arguably the most physiologically important endothelial mechanism of dilation and occurs in virtually every vascular bed. Recent data from our laboratory indicate that flow-mediated dilation (FMD) occurs in coronary arterioles from patients with coronary disease however it operates through a novel mechanism involving endothelial production of reactive oxygen species (ROS) including hydrogen peroxide (H2O2). Surprisingly the mitochondrial respiratory chain plays a necessary role in FMD in the human heart, however it is not known how mitochondria are involved in the transduction of mechanical shear stress on the surface of the endothelium to elicit dilation. Our overall hypothesis is that shear acting on endothelial cells through attached cytoskeletal elements stimulates release from the mitochondria of H2O2, an endothelial derived hyperpolarizing factor (EDHF). We shall test this hypothesis in three ways. First antimycin A and TNFalpha will be used to determine if pharmacological stimulation of mitochondrial ROS release can elicit dilation of human coronary arterioles. In separate studies, we shall use novel antioxidants targeted to the mitochondrial inner membrane to determine whether H2O2 generated from within the mitochondria is necessary for FMD. A bioassay system will confirm whether H2O2 is indeed an EDHF mediating FMD in the human coronary circulation. Second we will use immunohistochemistry and specific pharmacological and molecular approaches including siRNA to determine whether endothelial cytoskeletal elements play a necessary role in FMD and mitochondrial ROS generation. Third, we shall test the hypothesis that nitric oxide through its inhibitory effect on mitochondrial respiration reduces FMD in the human heart. This will be done using nitric oxide donors, measuring mitochondrial complex activity and ROS generation. These experiments may identify a pathway not previously described by which nitric oxide can inhibit EDHF-mediated dilation; namely, by blocking mitochondrial production of ROS. Collectively these aims address a novel mechanism of endothelium-dependent vasodilation involving mitochondrial generation of ROS, thus far reported only in human hearts. These studies should identify new links among cell processes including mechanotransduction, respiration, and redox signaling that regulate physiological events such as vasodilation.
Funding Period: 2006-01-01 - 2010-12-31
more information: NIH RePORT

Top Publications

  1. pmc Adverse alterations in mitochondrial function contribute to type 2 diabetes mellitus-related endothelial dysfunction in humans
    Tinoy J Kizhakekuttu
    Department of Medicine, Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Arterioscler Thromb Vasc Biol 32:2531-9. 2012
  2. pmc Regulation of endothelial function by mitochondrial reactive oxygen species
    Michael E Widlansky
    Department of Medicine, Cardiovascular Medicine Division and Department of Pharmacology, Medical College of Wisconsin, Milwaukee, Wisconsin
    Antioxid Redox Signal 15:1517-30. 2011
  3. pmc H2O2 is the transferrable factor mediating flow-induced dilation in human coronary arterioles
    Yanping Liu
    Office of Research, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA
    Circ Res 108:566-73. 2011
  4. pmc ROS-induced ROS release in vascular biology: redox-redox signaling
    Natalya S Zinkevich
    Cardiovascular Center, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
    Am J Physiol Heart Circ Physiol 301:H647-53. 2011
  5. pmc Soluble epoxide hydrolase contamination of specific catalase preparations inhibits epoxyeicosatrienoic acid vasodilation of rat renal arterioles
    Kathryn M Gauthier
    Department of Pharmacology and Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
    Am J Physiol Renal Physiol 301:F765-72. 2011
  6. pmc Regulation of the human coronary microcirculation
    Andreas M Beyer
    Department of Medicine, Cardiology Division Medical College of Wisconsin, Milwaukee, WI 53226, United States
    J Mol Cell Cardiol 52:814-21. 2012
  7. pmc Activation of endothelial TRPV4 channels mediates flow-induced dilation in human coronary arterioles: role of Ca2+ entry and mitochondrial ROS signaling
    Aaron H Bubolz
    Dept of Medicine, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA
    Am J Physiol Heart Circ Physiol 302:H634-42. 2012
  8. pmc H2O2-induced dilation in human coronary arterioles: role of protein kinase G dimerization and large-conductance Ca2+-activated K+ channel activation
    David X Zhang
    Department of Medicine, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, 53226, USA
    Circ Res 110:471-80. 2012
  9. pmc Nitric oxide synthase-dependent vasodilation of human subcutaneous arterioles correlates with noninvasive measurements of endothelial function
    Kodlipet Dharmashankar
    Department of Medicine, Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
    Am J Hypertens 25:528-34. 2012
  10. pmc Transient receptor potential channel activation and endothelium-dependent dilation in the systemic circulation
    David X Zhang
    Department of Medicine, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Rd Milwaukee, WI 53226, USA
    J Cardiovasc Pharmacol 57:133-9. 2011

Scientific Experts

Detail Information

Publications20

  1. pmc Adverse alterations in mitochondrial function contribute to type 2 diabetes mellitus-related endothelial dysfunction in humans
    Tinoy J Kizhakekuttu
    Department of Medicine, Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Arterioscler Thromb Vasc Biol 32:2531-9. 2012
    ..Mitochondrial dysfunction plays a key pathophysiological role in type 2 diabetes mellitus (T2DM). Data delineating relationships between mitochondrial and endothelial dysfunction in humans with T2DM are lacking...
  2. pmc Regulation of endothelial function by mitochondrial reactive oxygen species
    Michael E Widlansky
    Department of Medicine, Cardiovascular Medicine Division and Department of Pharmacology, Medical College of Wisconsin, Milwaukee, Wisconsin
    Antioxid Redox Signal 15:1517-30. 2011
    ..Future potential avenues of research in this field also are discussed...
  3. pmc H2O2 is the transferrable factor mediating flow-induced dilation in human coronary arterioles
    Yanping Liu
    Office of Research, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA
    Circ Res 108:566-73. 2011
    ..However, H(2)O(2) has never been shown to be the endothelium-dependent transferrable hyperpolarization factor (EDHF) in response to shear stress...
  4. pmc ROS-induced ROS release in vascular biology: redox-redox signaling
    Natalya S Zinkevich
    Cardiovascular Center, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
    Am J Physiol Heart Circ Physiol 301:H647-53. 2011
    ..This review will provide descriptions and examples of important mechanisms of RIRR...
  5. pmc Soluble epoxide hydrolase contamination of specific catalase preparations inhibits epoxyeicosatrienoic acid vasodilation of rat renal arterioles
    Kathryn M Gauthier
    Department of Pharmacology and Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
    Am J Physiol Renal Physiol 301:F765-72. 2011
    ..However, some commercial catalase preparations are contaminated with sEH, and these contaminated preparations diminish the biological activity of H(2)O(2) and EETs...
  6. pmc Regulation of the human coronary microcirculation
    Andreas M Beyer
    Department of Medicine, Cardiology Division Medical College of Wisconsin, Milwaukee, WI 53226, United States
    J Mol Cell Cardiol 52:814-21. 2012
    ..This article is part of a Special Issue entitled "Coronary Blood Flow"...
  7. pmc Activation of endothelial TRPV4 channels mediates flow-induced dilation in human coronary arterioles: role of Ca2+ entry and mitochondrial ROS signaling
    Aaron H Bubolz
    Dept of Medicine, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA
    Am J Physiol Heart Circ Physiol 302:H634-42. 2012
    ..Elucidation of this novel TRPV4-ROS pathway may improve our understanding of the pathogenesis of coronary artery disease and/or other cardiovascular disorders...
  8. pmc H2O2-induced dilation in human coronary arterioles: role of protein kinase G dimerization and large-conductance Ca2+-activated K+ channel activation
    David X Zhang
    Department of Medicine, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, 53226, USA
    Circ Res 110:471-80. 2012
    ..An important mode of action of H(2)O(2) involves the oxidation of cysteine residues in its target proteins, including protein kinase G (PKG)-Iα, thereby modulating their activities...
  9. pmc Nitric oxide synthase-dependent vasodilation of human subcutaneous arterioles correlates with noninvasive measurements of endothelial function
    Kodlipet Dharmashankar
    Department of Medicine, Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
    Am J Hypertens 25:528-34. 2012
    ..Limited data relating subcutaneous arteriolar endothelial function, cardiovascular risk factors, and noninvasive measurements of endothelial function currently exist...
  10. pmc Transient receptor potential channel activation and endothelium-dependent dilation in the systemic circulation
    David X Zhang
    Department of Medicine, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Rd Milwaukee, WI 53226, USA
    J Cardiovasc Pharmacol 57:133-9. 2011
    ....
  11. pmc Measuring FMD in the brachial artery: how important is QRS gating?
    Tinoy J Kizhakekuttu
    Cardiovascular Medicine Division, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    J Appl Physiol (1985) 109:959-65. 2010
    ..This finding may allow for simplification of FMD measurement and aid in the development of FMD as a potentially useful clinical tool...
  12. pmc Altered mitochondrial membrane potential, mass, and morphology in the mononuclear cells of humans with type 2 diabetes
    Michael E Widlansky
    Department of Medicine, Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Transl Res 156:15-25. 2010
    ..Furthermore, potentially clinically relevant perturbations in mitochondrial homeostasis in T2DM human mononuclear cells can be detected...
  13. pmc Bradykinin-induced dilation of human coronary arterioles requires NADPH oxidase-derived reactive oxygen species
    Brandon T Larsen
    Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
    Arterioscler Thromb Vasc Biol 29:739-45. 2009
    ..H2O2 mediates bradykinin (BK)-induced vasodilation and reduces bioavailability of epoxyeicosatrienoic acids (EETs); however, the cellular and enzymatic source of H2O2 is unknown...
  14. ncbi Epoxyeicosatrienoic acids, TRP channels, and intracellular Ca2+ in the vasculature: an endothelium-derived endothelium-hyperpolarizing factor?
    Brandon T Larsen
    Arterioscler Thromb Vasc Biol 27:2496-8. 2007
  15. pmc Endothelial cytoskeletal elements are critical for flow-mediated dilation in human coronary arterioles
    Yanping Liu
    The National Center for Research Resources, National Institutes of Health, Bethesda, MD, USA
    Med Biol Eng Comput 46:469-78. 2008
    ..58 +/- 7%). These results suggest that cytoskeletal elements are a critical component of the signaling mechanism linking endothelial shear stress and mitochondrial release of ROS in the human coronary microcirculation...
  16. pmc Transient receptor potential vanilloid type 4-deficient mice exhibit impaired endothelium-dependent relaxation induced by acetylcholine in vitro and in vivo
    David X Zhang
    Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA
    Hypertension 53:532-8. 2009
    ..These findings may provide novel insight into mechanisms of Ca2+ entry evoked by chemical agonists in endothelial cells...
  17. pmc Vascular control in humans: focus on the coronary microcirculation
    Yanping Liu
    National Center for Research Resources, NIH, Bethesda, MD, USA
    Basic Res Cardiol 104:211-27. 2009
    ..Unique properties of coronary arterioles in human vs. other species are discussed...
  18. pmc TRPV4-mediated endothelial Ca2+ influx and vasodilation in response to shear stress
    Suelhem A Mendoza
    Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA
    Am J Physiol Heart Circ Physiol 298:H466-76. 2010
    ....
  19. ncbi The mechanism of flow-induced dilation in human adipose arterioles involves hydrogen peroxide during CAD
    Shane A Phillips
    Cardiovascular Center, Dept of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA
    Am J Physiol Heart Circ Physiol 292:H93-100. 2007
    ..This study provides evidence that adverse microvascular changes during CAD are evident in human visceral adipose, a tissue associated with CAD...