Mechanisms of Microvascular Control and Coordination in Health and Disease

Summary

Principal Investigator: Gerald A Meininger
Abstract: DESCRIPTION (provided by applicant): This is a revised new Program Project application from an interactive group of experienced investigators consisting of 3 projects and 3 cores. The overall theme of this PPG is to understand how arterioles are regulated by interactions between cell integrins and extracellular matrix (ECM) proteins and how these interactions are disturbed by vascular disease. Over the last 12 years, program investigators published most of the early work establishing a key role for integrins in microvascular control. Recent insights by our investigative team have identified key integrins and ECM proteins setting the stage for major breakthroughs in this field that will significantly advance our understanding of this paradigm for microvascular control. A central premise of this PPG is that microvascular control in health and disease is influenced by properties of the ECM and ECM interactions with integrins on cells of the microvascular wall. Project 1 will examine the ability of vasoactive mediators to influence integrin-ECM adhesion and determine how adhesion is coordinated with microvascular smooth muscle cell (mVSMC) contraction and control of arteriole diameter. Project 2 will examine the ability of ECM proteins to signal through integrins and modulate Mvsmc membrane conductance of Ca2+ and K+ to control vasomotor tone. Project 3 examines a unique hypothesis that during inflammation emigrating leukocytes cause ECM degradation that generates integrin-binding signals that impair control of arterioles. Core A will provide administrative support for the PPG. For all projects, Cores B will provide imaging technology/support and Core C will provide for molecular and cell level technologies. Together, the projects will shape an integrated view of microvascular regulation using model systems that include freshly isolated mVSMC, isolated arterioles and microvascular network preparations. A multidisciplinary array of technical approaches ranging from atomic force microscopy, fluorescence microscopy, electrophysiology and molecular techniques will allow a comprehensive and systematic exploration of concepts. (End of Abstract)
Funding Period: 2010-03-22 - 2015-02-28
more information: NIH RePORT

Top Publications

  1. pmc AICAR preconditioning prevents postischemic leukocyte rolling and adhesion: role of K(ATP) channels and heme oxygenase
    F Spencer Gaskin
    Department of Medical Pharmacology and Physiology, University of Missouri Columbia, One Hospital Drive, Columbia, MO 65212, USA
    Microcirculation 16:167-76. 2009
  2. pmc Influence of membrane cholesterol and substrate elasticity on endothelial cell spreading behavior
    Zhongkui Hong
    Department of Physics and Astronomy, University of Missouri, Columbia, Missouri 65211, USA
    J Biomed Mater Res A 101:1994-2004. 2013
  3. pmc Spontaneous bursts of muscle sympathetic nerve activity decrease leg vascular conductance in resting humans
    Seth T Fairfax
    Department of Biomedical Sciences, University of Missouri, Columbia, MO 65212, USA
    Am J Physiol Heart Circ Physiol 304:H759-66. 2013
  4. pmc Mechanisms underlying regional differences in the Ca2+ sensitivity of BK(Ca) current in arteriolar smooth muscle
    Yan Yang
    Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA
    J Physiol 591:1277-93. 2013
  5. pmc Prolonged vasoconstriction of resistance arteries involves vascular smooth muscle actin polymerization leading to inward remodelling
    Marius C Staiculescu
    Dalton Cardiovascular Research Center, University of Missouri Columbia, 134 Research Park Dr, Columbia, MO 65211, USA
    Cardiovasc Res 98:428-36. 2013
  6. pmc Amyloid-β peptide on sialyl-Lewis(X)-selectin-mediated membrane tether mechanics at the cerebral endothelial cell surface
    Sholpan Askarova
    Department of Biological Engineering, University of Missouri, Columbia, Missouri, USA
    PLoS ONE 8:e60972. 2013
  7. pmc The role of α-adrenergic receptors in mediating beat-by-beat sympathetic vascular transduction in the forearm of resting man
    Seth T Fairfax
    Biomedical Sciences, University of Missouri, Columbia, MO 65212, USA
    J Physiol 591:3637-49. 2013
  8. pmc Increased vascular smooth muscle cell stiffness: a novel mechanism for aortic stiffness in hypertension
    Nancy L Sehgel
    Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey
    Am J Physiol Heart Circ Physiol 305:H1281-7. 2013
  9. pmc Preconditioning with soluble guanylate cyclase activation prevents postischemic inflammation and reduces nitrate tolerance in heme oxygenase-1 knockout mice
    Walter Z Wang
    Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri and
    Am J Physiol Heart Circ Physiol 305:H521-32. 2013
  10. pmc Influence of spontaneously occurring bursts of muscle sympathetic nerve activity on conduit artery diameter
    Seth T Fairfax
    Biomedical Sciences, University of Missouri, Columbia, Missouri
    Am J Physiol Heart Circ Physiol 305:H867-74. 2013

Research Grants

  1. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
  2. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
  3. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
  4. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
  5. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
  6. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
  7. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013

Detail Information

Publications30

  1. pmc AICAR preconditioning prevents postischemic leukocyte rolling and adhesion: role of K(ATP) channels and heme oxygenase
    F Spencer Gaskin
    Department of Medical Pharmacology and Physiology, University of Missouri Columbia, One Hospital Drive, Columbia, MO 65212, USA
    Microcirculation 16:167-76. 2009
    ..The major aim of this study was to examine the role of ATP-sensitive potassium (K(ATP)) channels and heme oxygenase as mediators of the antiadhesive effects of AICAR-PC during I/R 24 hours later...
  2. pmc Influence of membrane cholesterol and substrate elasticity on endothelial cell spreading behavior
    Zhongkui Hong
    Department of Physics and Astronomy, University of Missouri, Columbia, Missouri 65211, USA
    J Biomed Mater Res A 101:1994-2004. 2013
    ..These observations indicate that membrane cholesterol plays an important role in cell spreading on soft biomimetic materials constructed with appropriate elasticity...
  3. pmc Spontaneous bursts of muscle sympathetic nerve activity decrease leg vascular conductance in resting humans
    Seth T Fairfax
    Department of Biomedical Sciences, University of Missouri, Columbia, MO 65212, USA
    Am J Physiol Heart Circ Physiol 304:H759-66. 2013
    ....
  4. pmc Mechanisms underlying regional differences in the Ca2+ sensitivity of BK(Ca) current in arteriolar smooth muscle
    Yan Yang
    Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA
    J Physiol 591:1277-93. 2013
    ..Functionally, this leads both to higher Ca(2+) sensitivity and NPo for BKCa channels in the cerebral vasculature relative to that of skeletal muscle...
  5. pmc Prolonged vasoconstriction of resistance arteries involves vascular smooth muscle actin polymerization leading to inward remodelling
    Marius C Staiculescu
    Dalton Cardiovascular Research Center, University of Missouri Columbia, 134 Research Park Dr, Columbia, MO 65211, USA
    Cardiovasc Res 98:428-36. 2013
    ..Here we investigated the role of vascular smooth muscle (VSM) actin polymerization on agonist-induced vasoconstriction and development of inward remodelling...
  6. pmc Amyloid-β peptide on sialyl-Lewis(X)-selectin-mediated membrane tether mechanics at the cerebral endothelial cell surface
    Sholpan Askarova
    Department of Biological Engineering, University of Missouri, Columbia, Missouri, USA
    PLoS ONE 8:e60972. 2013
    ....
  7. pmc The role of α-adrenergic receptors in mediating beat-by-beat sympathetic vascular transduction in the forearm of resting man
    Seth T Fairfax
    Biomedical Sciences, University of Missouri, Columbia, MO 65212, USA
    J Physiol 591:3637-49. 2013
    ..1 ± 0.7% and -0.7 ± 0.8%, respectively; P < 0.001 vs. normal saline). These findings indicate that spontaneous MSNA bursts evoke robust beat-by-beat decreases in FVC that are exclusively mediated via α-adrenergic receptors...
  8. pmc Increased vascular smooth muscle cell stiffness: a novel mechanism for aortic stiffness in hypertension
    Nancy L Sehgel
    Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey
    Am J Physiol Heart Circ Physiol 305:H1281-7. 2013
    ..This is the first study demonstrating that stiffness of individual vascular smooth muscle cells mediates vascular stiffness in hypertension, a novel concept, which may elucidate new therapies for hypertension and for vascular stiffness...
  9. pmc Preconditioning with soluble guanylate cyclase activation prevents postischemic inflammation and reduces nitrate tolerance in heme oxygenase-1 knockout mice
    Walter Z Wang
    Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri and
    Am J Physiol Heart Circ Physiol 305:H521-32. 2013
    ..Collectively these actions would contribute to increased nitrate sensitivity and vascular function...
  10. pmc Influence of spontaneously occurring bursts of muscle sympathetic nerve activity on conduit artery diameter
    Seth T Fairfax
    Biomedical Sciences, University of Missouri, Columbia, Missouri
    Am J Physiol Heart Circ Physiol 305:H867-74. 2013
    ....
  11. pmc β1-integrin is essential for vasoregulation and smooth muscle survival in vivo
    Kirsten A Turlo
    From the Department of Molecular, Cellular, and Developmental Biology K A T, M L I A and Molecular Biology Institute J S, University of California, Los Angeles, CA Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO P B, A W J, R J K, S S S Interfaculty Institute of Biochemistry, University of Tuebingen, Tuebingen, Germany R F and Dalton Cardiovascular Research Center, Columbia, MO A W J, R J K, S S S
    Arterioscler Thromb Vasc Biol 33:2325-35. 2013
    ..Integrins contribute to vascular morphogenesis through regulation of adhesion and assembly of the extracellular matrix. However, the role of β1-integrin in the mature vascular wall is less clear...
  12. pmc Vasoactive agonists exert dynamic and coordinated effects on vascular smooth muscle cell elasticity, cytoskeletal remodelling and adhesion
    Zhongkui Hong
    Dalton Cardiovascular Center, University of Missouri, 134 Research Park Dr, Columbia, MO 65211, USA
    J Physiol 592:1249-66. 2014
    ..Thus, vasoactive agonists probably invoke unique mechanisms that dynamically alter the behaviour and structure of both the VSMC cytoskeleton and focal adhesions to efficiently support the normal contractile behaviour of VSMCs...
  13. ncbi N-cadherin, a vascular smooth muscle cell-cell adhesion molecule: function and signaling for vasomotor control
    Zhe Sun
    Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
    Microcirculation 21:208-18. 2014
    ..In particular, attention is given to applications of this knowledge to VSM. The review points to the need for more research effort that is directed at understanding the role of N-cadherins in the regulation of vascular function. ..
  14. pmc Does C-reactive protein contribute to atherothrombosis via oxidant-mediated release of pro-thrombotic factors and activation of platelets?
    Zhuo Zhang
    Drug Discovery Research Center, Luzhou Medical College Luzhou, China
    Front Physiol 3:433. 2012
    ..Collectively, the available data provide strong support for ROS playing an important intermediary role in the relationship between CRP and atherothrombosis...
  15. pmc Atomic force microscopy to characterize binding properties of α7-containing nicotinic acetylcholine receptors on neurokinin-1 receptor-expressing medullary respiratory neurons
    Catharine G Clark
    Dalton Cardiovascular Research Center and Departments of Biomedical Sciences, University of Missouri, Columbia, MO 65211, USA
    Exp Physiol 98:415-24. 2013
    ..Moreover, these data demonstrate that nicotine exposure decreases the binding probability of α7 subunit-containing nAChRs...
  16. pmc Increased brachial artery retrograde shear rate at exercise onset is abolished during prolonged cycling: role of thermoregulatory vasodilation
    Grant H Simmons
    E102 Veterinary Medicine Bldg, Univ of Missouri, Columbia, MO 65211, USA
    J Appl Physiol (1985) 110:389-97. 2011
    ..9 ± 12.5 s(-1)). We conclude that increased brachial artery retrograde SR at the onset of leg cycling subsequently returns toward baseline values due in part to thermoregulatory cutaneous vasodilation during prolonged exercise...
  17. pmc Spatial association of the Cav1.2 calcium channel with α5β1-integrin
    Jun Tzu Chao
    Dept of Medical Pharmacology and Physiology, M451 Med Sci Bldg, Univ of Missouri, Columbia, 1 Hospital Dr, Columbia, MO 65211, USA
    Am J Physiol Cell Physiol 300:C477-89. 2011
    ..These findings provide new evidence for how interactions between α(5)β(1)-integrin and FN can modulate Ca(L) entry and consequently alter the physiological function of multiple types of excitable cells...
  18. pmc Intravital macrozoom imaging and automated analysis of endothelial cell calcium signals coincident with arteriolar dilation in Cx40(BAC) -GCaMP2 transgenic mice
    Pooneh Bagher
    Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri 65212, USA
    Microcirculation 18:331-8. 2011
    ..Our goal was to develop methods enabling automated analyses for accurately and objectively determining the dynamic relationship between EC Ca(2+) responses and arteriolar diameter in vivo...
  19. pmc Brachial artery vasodilatation during prolonged lower limb exercise: role of shear rate
    Jaume Padilla
    Department of Biomedical Sciences, E102 Veterinary Medicine, 1600 East Rollins Road, University of Missouri, Columbia, MO 65211, USA
    Exp Physiol 96:1019-27. 2011
    ..These results are consistent with the hypothesis that shear stress plays a key role in signalling brachial artery vasodilatation during dynamic leg exercise...
  20. pmc Hydrogen sulfide preconditioning or neutrophil depletion attenuates ischemia-reperfusion-induced mitochondrial dysfunction in rat small intestine
    Yajun Liu
    Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri 65212, USA
    Am J Physiol Gastrointest Liver Physiol 302:G44-54. 2012
    ..In addition, NaHS-PC prevents postischemic mitochondrial dysfunction (but not inflammation) by a BK(Ca) channel-dependent mechanism...
  21. pmc Spatial distribution and mechanical function of elastin in resistance arteries: a role in bearing longitudinal stress
    Philip S Clifford
    Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA
    Arterioscler Thromb Vasc Biol 31:2889-96. 2011
    ..Our objective was to examine the hypothesis that adventitial elastin fibers are dominant in vessels subject to longitudinal stretch...
  22. pmc Moderate ethanol ingestion and cardiovascular protection: from epidemiologic associations to cellular mechanisms
    Maike Krenz
    Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO 65212, USA
    J Mol Cell Cardiol 52:93-104. 2012
    ....
  23. pmc Mechanotransduction through fibronectin-integrin focal adhesion in microvascular smooth muscle cells: is calcium essential?
    Zhe Sun
    Dalton Cardiovascular Research Center and Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65211, USA
    Am J Physiol Heart Circ Physiol 302:H1965-73. 2012
    ..On the other hand, our data support a role for Rho-linked signaling mechanism involved in mechanotransduction leading to focal contraction that is independent of the need for a global increase in VSMC Ca(2+)...
  24. pmc Temporal analysis of vascular smooth muscle cell elasticity and adhesion reveals oscillation waveforms that differ with aging
    Yi Zhu
    Dalton Cardiovascular Res Center and Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65211, USA
    Aging Cell 11:741-50. 2012
    ..The oscillatory behavior suggests that mechanisms governing elasticity and adhesion are coupled and affected differentially during aging, which may link these events to changes in vascular stiffness...
  25. pmc Arteriolar vascular smooth muscle cells: mechanotransducers in a complex environment
    Michael A Hill
    Dalton Cardiovascular Research Center and Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65211, USA
    Int J Biochem Cell Biol 44:1505-10. 2012
    ..Importantly, it is argued that the contractile properties of small artery VSMCs reflect an intimate and integrated interaction with their extracellular environment and the three-dimensional structure of the vessel wall...
  26. pmc Coordination of fibronectin adhesion with contraction and relaxation in microvascular smooth muscle
    Zhongkui Hong
    Dalton Cardiovascular Research Center, University of Missouri, 134 Research Park Dr, Columbia, MO 65211, USA
    Cardiovasc Res 96:73-80. 2012
    ....
  27. pmc Cell biology of ischemia/reperfusion injury
    Theodore Kalogeris
    Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, USA
    Int Rev Cell Mol Biol 298:229-317. 2012
    ....
  28. pmc Mitochondrial reactive oxygen species: a double edged sword in ischemia/reperfusion vs preconditioning
    Theodore Kalogeris
    Department of Medical Pharmacology and Physiology, School of Medicine, Dalton Cardiovascular Research Center, University of Missouri, 1 Hospital Drive, Columbia, MO 65212 0001, United States of America
    Redox Biol 2:702-14. 2014
    ....

Research Grants30

  1. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
    ..These projects are supported by 3 Cores: Core A: The Administrative Core;Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core. (End of Abstract) ..
  2. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  3. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  4. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  5. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
    ..abstract_text> ..
  6. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
    ..A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF. ..
  7. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..