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. 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
  2. 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
  3. ncbi 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
  4. ncbi 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
  5. ncbi 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
  6. ncbi 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

Scientific Experts

  • David X Zhang
  • Shane A Phillips
  • Yanping Liu
  • David D Gutterman
  • Suelhem A Mendoza
  • Aaron H Bubolz
  • Brandon T Larsen
  • Makoto Suzuki
  • David A Wilcox
  • Juan Fang
  • Rongshan Li
  • Hongwei Li

Detail Information

Publications6

  1. 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...
  2. 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
  3. ncbi 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...
  4. ncbi 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...
  5. ncbi 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...
  6. ncbi 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
    ....