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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL095486-03
Application #
8245064
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Mcdonald, Cheryl
Project Start
2010-03-22
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$1,693,159
Indirect Cost
$568,289
Name
University of Missouri-Columbia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Sehgel, Nancy L; Sun, Zhe; Hong, Zhongkui et al. (2015) Augmented vascular smooth muscle cell stiffness and adhesion when hypertension is superimposed on aging. Hypertension 65:370-7
Hong, Zhongkui; Sun, Zhe; Li, Min et al. (2014) Vasoactive agonists exert dynamic and coordinated effects on vascular smooth muscle cell elasticity, cytoskeletal remodelling and adhesion. J Physiol 592:1249-66
Kalogeris, Theodore; Bao, Yimin; Korthuis, Ronald J (2014) Mitochondrial reactive oxygen species: a double edged sword in ischemia/reperfusion vs preconditioning. Redox Biol 2:702-14
Sun, Zhe; Parrish, Alan R; Hill, Michael A et al. (2014) N-cadherin, a vascular smooth muscle cell-cell adhesion molecule: function and signaling for vasomotor control. Microcirculation 21:208-18
Kalogeris, Theodore J; Baines, Christopher; Korthuis, Ronald J (2014) Adenosine prevents TNF?-induced decrease in endothelial mitochondrial mass via activation of eNOS-PGC-1? regulatory axis. PLoS One 9:e98459
Nourian, Zahra; Li, Min; Leo, M Dennis et al. (2014) Large conductance Ca2+-activated K+ channel (BKCa) ?-subunit splice variants in resistance arteries from rat cerebral and skeletal muscle vasculature. PLoS One 9:e98863
Fairfax, Seth T; Holwerda, Seth W; Credeur, Daniel P et al. (2013) The role of ýý-adrenergic receptors in mediating beat-by-beat sympathetic vascular transduction in the forearm of resting man. J Physiol 591:3637-49
Korthuis, Ronald J; Kalogeris, Theodore (2013) TRPing up reperfusion: neutrophil TRPM2 channels exacerbate necrosis and contractile dysfunction in post-ischaemic myocardium. Cardiovasc Res 97:197-9
Hong, Zhongkui; Ersoy, Ilker; Sun, Mingzhai et al. (2013) Influence of membrane cholesterol and substrate elasticity on endothelial cell spreading behavior. J Biomed Mater Res A 101:1994-2004
Fairfax, Seth T; Padilla, Jaume; Vianna, Lauro C et al. (2013) Spontaneous bursts of muscle sympathetic nerve activity decrease leg vascular conductance in resting humans. Am J Physiol Heart Circ Physiol 304:H759-66

Showing the most recent 10 out of 27 publications