Coronary ion channels, gender and vasoreactivity

Summary

Principal Investigator: DOUGLAS BOWLES
Abstract: Recent prospective clinical trials have underscored our lack of knowledge with regard to the effect of gender and sex hormones on the coronary vasculature, especially at the cellular/molecular level. Sex hormones exert profound influence on vascular smooth muscle physiology, including proliferation, ion channel activity and channel expression. Coronary smooth muscle (CSM) ion channel activity is central to both regulation of coronary blood flow and progression of vascular disease. We have demonstrated that CSM calcium and potassium channel activities are strongly influenced by gender. This study will determine the mechanism for gender-specific differences in CSM voltage-gated calcium (VGCC) and K channel activity and the consequent effects on intracellular calcium (Cai) regulation and vasoreactivity. The overall hypothesis is that coronary arterial reactivity in males is greater due to a testosterone (TST)-dependent increase in VGCC synthesis and PKC-dependent activity resulting in an enhanced propensity for coronary vasospasm (CVS). Both in vivo (intact, gonadectomized and hormone-replaced swine) and in vitro techniques will be used to determine the role of gender, TST and estrogen (E2) in regulating CSM ion channel activity and coronary arterial reactivity. Aim 1 will determine the mechanism of gender and sex hormone induced changes in VGCC activity and expression using electrophysiology, immunoblot and RT-PCR. As both vasoreactivity and VGCC activity are modulated by PKC, gender and sex hormone effects on PKC regulation of VGCC will also be examined. As the effect of VGCC activity on Cai and contraction is modulated via coupling to K channels and cellular calcium buffering, Aim 2 will determine the effect of sex-specific differences in VGCC activity on Ca-activated (BK) and voltage-dependent K current (Kv) and Cai using simultaneous voltage clamp and microfluorometry. The effect of sex-specific differences in VGCC activity on macro- and microvascular reactivity under both physiological and pathophysiological conditions will be assessed in vitro and in vivo in Aim 3. A model of CVS will be used to assess the role of sex-specific differences in VGCC activity on the progression and severity of vascular disease. The goal of this research is to determine gender-related cellular and molecular differences in CSM as they relate to gender differences in propensity for coronary disease.
Funding Period: 2004-07-01 - 2010-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Excitation-transcription coupling in arterial smooth muscle
    Brian R Wamhoff
    Biomedical Sciences, Veterinary School of Medicine, University of Missouri, Columbia, MO, USA
    Circ Res 98:868-78. 2006
  2. pmc Endogenous testosterone attenuates neointima formation after moderate coronary balloon injury in male swine
    Darla L Tharp
    Department of Biomedical Sciences, University of Missouri, Columbia, MO 65211, USA
    Cardiovasc Res 82:152-60. 2009
  3. pmc Negligible contribution of coronary adventitial fibroblasts to neointimal formation following balloon angioplasty in swine
    Bradley S Fleenor
    Department of Biomedical Sciences, University of Missouri, Columbia, MO 65211, USA
    Am J Physiol Heart Circ Physiol 296:H1532-9. 2009
  4. pmc Focused in vivo delivery of plasmid DNA to the porcine vascular wall via intravascular ultrasound destruction of microbubbles
    Linsey C Phillips
    Biomedical Engineering, Robert M Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA
    J Vasc Res 47:270-4. 2010
  5. ncbi Ovariectomy increases L-type Ca(2+) channel activity in porcine coronary smooth muscle
    Darla L Tharp
    From the 1Department of Biomedical Sciences, 2Dalton Cardiovascular Research Center, and 3Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO
    Menopause 21:661-8. 2014

Detail Information

Publications5

  1. ncbi Excitation-transcription coupling in arterial smooth muscle
    Brian R Wamhoff
    Biomedical Sciences, Veterinary School of Medicine, University of Missouri, Columbia, MO, USA
    Circ Res 98:868-78. 2006
    ..In addition, we discuss the potential role of IK channels and TRPC in ET-coupling as potential mediators of SMC phenotypic modulation, ie, negatively regulate SMC differentiation marker genes, in vascular disease...
  2. pmc Endogenous testosterone attenuates neointima formation after moderate coronary balloon injury in male swine
    Darla L Tharp
    Department of Biomedical Sciences, University of Missouri, Columbia, MO 65211, USA
    Cardiovasc Res 82:152-60. 2009
    ..The purpose of the present study was to determine whether endogenous testosterone limits coronary neointima (NI) formation in a porcine model of post-angioplasty restenosis...
  3. pmc Negligible contribution of coronary adventitial fibroblasts to neointimal formation following balloon angioplasty in swine
    Bradley S Fleenor
    Department of Biomedical Sciences, University of Missouri, Columbia, MO 65211, USA
    Am J Physiol Heart Circ Physiol 296:H1532-9. 2009
    ....
  4. pmc Focused in vivo delivery of plasmid DNA to the porcine vascular wall via intravascular ultrasound destruction of microbubbles
    Linsey C Phillips
    Biomedical Engineering, Robert M Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA
    J Vasc Res 47:270-4. 2010
    ..Microbubble contrast agents have been shown to increase gene transfection in vivo in the presence of ultrasound...
  5. ncbi Ovariectomy increases L-type Ca(2+) channel activity in porcine coronary smooth muscle
    Darla L Tharp
    From the 1Department of Biomedical Sciences, 2Dalton Cardiovascular Research Center, and 3Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO
    Menopause 21:661-8. 2014
    ..Therefore, the purpose of the current study was to determine the effect of ovariectomy (OVX) on L-type Ca channel activity and expression in female Yucatan miniature swine...