Microvascular hyperpermeability represents an important injurious process underlying the development ofmany inflammatory diseases including diabetic complications. The long-term goal of our research program isto understand the cellular and molecular mechanisms in the regulation of microvascular barrier functionunder physiological and pathological conditions. As an integral component of the program, this project isdesigned to elucidate the signaling pathways and molecular mechanisms responsible for microvascularhyperpermeability during development of diabetes, a disease that affects a large population with highmorbidity and mortality resulting from complications characterized by microvascular injury. Our centralhypothesis states that diabetes upregulates PKCbeta in microvascular endothelium at multiple levels viaMAPK-stimulated gene expression, PDK1-potentiated catalytic activity, and DAG-mediated kinase activation.We further propose that upregulated PKCbeta increases the paracellular permeability of venular endotheliumby inducing endothelial cell contraction via the GDI-RhoA-ROCK cascade coupled with intercellular junctiondisorganization triggered by beta-catenin phosphorylation and VE-cadherin dissociation.
Three specific aims are proposed: 1) to unequivocally establish the role of PKCbeta in microvascular leakage during diabetes; 2)to characterize the signaling mechanisms of PKCbeta upregulation in diabetic pigs; and 3) to elucidate themolecular basis of PKCbeta-elicited microvascular hyperpermeability.
These aims will be accomplishedthrough a multifaceted molecular physiology approach that incorporates molecular techniques with functionalanalyses at the microvascular level. A human-relevant pig model of diabetes will serve as the primary modelfor quantitative assessment of endothelial barrier function in intact microvessels. Data derived from this studywill provide new insights into the pathogenesis of diabetic microvascular complications. Identification of theprecise molecular mechanisms responsible for PKC-induced end-point injury may lead to a new avenue forsearching therapeutic targets. Based on this study, a future direction of our research efforts will be directedto the development of molecular probes and therapies for diagnosis and treatment of microvascular leakageassociated with chronic inflammatory diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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Srinivas, Pothur R
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University of South Florida
Schools of Medicine
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Sun, Chongxiu; Beard Jr, Richard S; McLean, Danielle L et al. (2013) ADAM15 deficiency attenuates pulmonary hyperpermeability and acute lung injury in lipopolysaccharide-treated mice. Am J Physiol Lung Cell Mol Physiol 304:L135-42
Rigor, Robert R; Shen, Qiang; Pivetti, Christopher D et al. (2013) Myosin light chain kinase signaling in endothelial barrier dysfunction. Med Res Rev 33:911-33
Yuan, Sarah Y; Shen, Qiang; Rigor, Robert R et al. (2012) Neutrophil transmigration, focal adhesion kinase and endothelial barrier function. Microvasc Res 83:82-8
Sun, Chongxiu; Wu, Mack H; Lee, Eugene S et al. (2012) A disintegrin and metalloproteinase 15 contributes to atherosclerosis by mediating endothelial barrier dysfunction via Src family kinase activity. Arterioscler Thromb Vasc Biol 32:2444-51
Sun, Chongxiu; Wu, Mack H; Yuan, Sarah Y (2011) Nonmuscle myosin light-chain kinase deficiency attenuates atherosclerosis in apolipoprotein E-deficient mice via reduced endothelial barrier dysfunction and monocyte migration. Circulation 124:48-57
Lee, Eugene S; Shen, Qiang; Pitts, Robert L et al. (2010) Vein tissue expression of matrix metalloproteinase as biomarker for hemodialysis arteriovenous fistula maturation. Vasc Endovascular Surg 44:674-9
Shen, Qiang; Rigor, Robert R; Pivetti, Christopher D et al. (2010) Myosin light chain kinase in microvascular endothelial barrier function. Cardiovasc Res 87:272-80
Sun, Chongxiu; Wu, Mack H; Guo, Mingzhang et al. (2010) ADAM15 regulates endothelial permeability and neutrophil migration via Src/ERK1/2 signalling. Cardiovasc Res 87:348-55
Shen, Qiang; Wu, Mack H; Yuan, Sarah Y (2009) Endothelial contractile cytoskeleton and microvascular permeability. Cell Health Cytoskelet 2009:43-50
Kumar, Puneet; Shen, Qiang; Pivetti, Christopher D et al. (2009) Molecular mechanisms of endothelial hyperpermeability: implications in inflammation. Expert Rev Mol Med 11:e19

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