Disseminated microvascular thromboses such as disseminated intravascular coagulation (DIC) frequently occurs in severe systemic inflammation and sepsis. Septic patients with DIC may manifest a prothrombotic state that lead to a sudden widespread microvascular thrombosis, occluding the vessels. The resultant microvascular occlusion cause multiple organ failure (MOF) and may result in death. Autopsies of patients who succumbed to sepsis-associated DIC demonstrated a widespread fibrin-rich and von Willebrand factor (VWF)-rich microthrombi in organs. This is, in part, because of the massive generation of fibrin that leads to fibrin deposition in the microvasculature and the significant increase in the secretion of the prothrombotic ultra large (UL) VWF strings from endothelial cells (ECs). These hyperadhesive VWF strings anchored on ECs and the deposited fibrin can capture circulating platelets, causing microvascular occlusion. We have identified vimentin (Vim), an intermediate filament that is also expressed on the surface of ECs, as ligand for VWF. Both Vim and fibrin bind to the A2 domain of VWF. Consequently, the recombinant A2 protein (A2 domain of VWF) inhibits Vim- and fibrin-VWF interactions, prevents the ULVWF strings formation on the inflamed ECs, reduces VWF-mediated flow-dependent platelet adhesion to fibrin, and inhibits platelet-fibrin clots formation. Moreover, the A2 protein ameliorated the prothrombotic state in a mouse model of endotoxemia-induced DIC given 1.5 hour after the endotoxin (lipopolysaccharide, LPS) insult. In these mice, the A2 protein increased survival, reduced disseminated fibrin-rich and VWF-rich microthrombi, prevented infiltration of neutrophils into the lung, and dampened proinflammatory cytokines. Lastly, the A2 protein activated protein phosphatase 2A and decreased phosphorylation of PKC and AKT in LPS-stimulated ECs in vitro. Therefore, this application explores the therapeutic potential of the novel A2 protein that counteracts deleterious effects of prothrombotic, and proinflammatory pathways activated at endothelium. We propose three aims:
Aim 1 will investigate how interaction of Vim and fibrin with ULVWF contributes to microvascular thrombosis;
Aim 2 will dissect how A2 protein dampens LPS-induced signaling and functions in ECs;
Aim 3 will determine the effect of A2 protein in porcine models of MOF with disseminated microvascular thromboses. These studies will reveal a novel role for Vim in microvascular thrombosis and the potential utility of the A2 protein as a new therapeutic agent for conditions associated with disseminated microvascular thromboses and MOF.

Public Health Relevance

The objective of this proposal is to investigate the effect of the interaction between the isolated A2 domain of von Willebrand factor and vimentin or fibrin on the endothelium in response to inflammation. This work will lay the foundation for the development of potential anti- inflammatory agents derived from the A2 protein, targeting vimentin and fibrin in inflammation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Koduri, Sailaja
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Baylor College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
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Vijayan, K Vinod (2018) Myosin IIa signal von Willebrand factor release. Blood 131:592-593
Fasipe, Titilope A; Hong, Sung-Ha; Da, Qi et al. (2018) Extracellular Vimentin/VWF (von Willebrand Factor) Interaction Contributes to VWF String Formation and Stroke Pathology. Stroke 49:2536-2540
Lam, Fong W; Da, Qi; Guillory, Bobby et al. (2018) Recombinant Human Vimentin Binds to P-Selectin and Blocks Neutrophil Capture and Rolling on Platelets and Endothelium. J Immunol 200:1718-1726
Valladolid, Christian; Yee, Andrew; Cruz, Miguel A (2018) von Willebrand Factor, Free Hemoglobin and Thrombosis in ECMO. Front Med (Lausanne) 5:228
Pradhan, Subhashree; Khatlani, Tanvir; Nairn, Angus C et al. (2017) The heterotrimeric G protein G?1 interacts with the catalytic subunit of protein phosphatase 1 and modulates G protein-coupled receptor signaling in platelets. J Biol Chem 292:13133-13142
Dasgupta, Swapan K; Le, Anhquyen; Vijayan, K Vinod et al. (2017) Dasatinib inhibits actin fiber reorganization and promotes endothelial cell permeability through RhoA-ROCK pathway. Cancer Med 6:809-818
Carcillo, Joseph A; Podd, Bradley; Aneja, Rajesh et al. (2017) Pathophysiology of Pediatric Multiple Organ Dysfunction Syndrome. Pediatr Crit Care Med 18:S32-S45
Yao, Hui; He, Guangchun; Chen, Chao et al. (2017) PAI1: a novel PP1-interacting protein that mediates human plasma's anti-apoptotic effect in endothelial cells. J Cell Mol Med 21:2068-2076
Da, Q; Shaw, T; Pradhan, S et al. (2017) Disruption of protein complexes containing protein phosphatase 2B and Munc18c reduces the secretion of von Willebrand factor from endothelial cells. J Thromb Haemost 15:1032-1039
Ince, Can; Mayeux, Philip R; Nguyen, Trung et al. (2016) THE ENDOTHELIUM IN SEPSIS. Shock 45:259-70

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