Coronary microvascular exchange plays an essential role in the maintenance of normal cardiac function. In acute inflammation and myocardial ischemia-reperfusion, neutrophil adhesion to postcapillary venular endothelium followed by an increase in venular permeability comprises a common pathophysiological consequence in the development of myocardial dysfunction. Although much work has been dedicated to the clarification of neutrophil-derived agonists and second messengers, little is known about their molecular targets. Within this context, whether activated neutrophils affect microvascular barrier function by altering the structural and functional integrity of the endothelium remains elusive. Therefore, the overall goal of this study is to identify at molecular levels the signaling mechanism that controls the endothelial hyperpermeability response to activated neutrophils. Corresponding to this goal is the major hypothesis that neutrophil- induced barrier dysfunction occurs through a chain of events in the endothelium from cytoskeletal reorganization to junctional disorganization, which ultimately facilitate transendothelial flux of fluid and proteins. Specifically, three hypotheses will be tested: (1) activated neutrophils trigger the cytoskeletal contractile process through myosin light chain phosphorylation, (2) activated neutrophils downregulate the endothelial adherence junction through phosphorylation and dissociation of VE-cadherin/beta-catenin complex, and (3) activated neutrophils promote anchorage-dependent cell contraction through the formation and redistribution of focal adhesions. To test these hypotheses, several advanced experimental approaches will be employed, including the intact perfused coronary venule preparation, the cultured venular endothelial monolayer model, western blot analysis, fluorescence immunocytochemistry, DNA and protein transfection, and dominant negative inhibition approaches. The study will provide a new insight into the molecular pathobiology of inflammatory and ischemic heart diseases. Identification of specific target proteins of activated neutrophils will enhance the development of therapeutic strategies to effectively inhibit the deleterious process of edema without suppressing the beneficial effects of inflammatory responses.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Texas A&M University
Schools of Medicine
College Station
United States
Zip Code
Beard Jr, Richard S; Haines, Ricci J; Wu, Kevin Y et al. (2014) Non-muscle Mlck is required for ?-catenin- and FoxO1-dependent downregulation of Cldn5 in IL-1?-mediated barrier dysfunction in brain endothelial cells. J Cell Sci 127:1840-53
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
Lee, Eugene S; Van Spyk, Elyse N; Chun, Kevin C et al. (2012) Monocytic adhesion molecule expression and monocyte-endothelial cell dysfunction are increased in patients with peripheral vascular disease versus patients with abdominal aortic aneurysms. J Surg Res 177:373-81
Guo, Mingzhang; Yuan, Sarah Y; Frederich, Bert J et al. (2012) Role of non-muscle myosin light chain kinase in neutrophil-mediated intestinal barrier dysfunction during thermal injury. Shock 38:436-43
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
Rigor, Robert R; Beard Jr, Richard S; Litovka, Olesya P et al. (2012) Interleukin-1?-induced barrier dysfunction is signaled through PKC-? in human brain microvascular endothelium. Am J Physiol Cell Physiol 302:C1513-22
Lee, Eugene S; Shen, Qiang; Pitts, Robert L et al. (2011) Serum metalloproteinases MMP-2, MMP-9, and metalloproteinase tissue inhibitors in patients are associated with arteriovenous fistula maturation. J Vasc Surg 54:454-9; discussion 459-60
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

Showing the most recent 10 out of 44 publications