Lung vascular endothelial barrier function is regulated primarily by adherens junctions (AJs) consisting of VE- cadherin, which mediates adhesion of endothelial cells through homotypic interaction, and associated catenins. Recently, another VE-cadherin partner Vascular Endothelial Protein Tyrosine Phosphatase, VE-PTP, has been identified in regulating endothelial barrier function. Disassembly of AJs through internalization and subsequent degradation of VE-cadherin disrupts the endothelial barrier resulting severe intractable protein-rich pulmonary edema, the central pathogenic feature of ARDS. Restoration of the endothelial barrier is essential for resolving edema, yet the mechanisms underlying re-assembly of AJs are poorly understood. Based on our Supporting Data, in Project 1 we posit that VE-PTP is a central regulator of re-assembly of AJs that plays a critical role in restoring endothelial barrier function through its ability to stabilize VE-cadherin at AJs. We also showed that signaling via Hypoxia-Inducible Factors (HIFs) was required for the synthesis of VE-PTP. Notably, in addition to VE-PTP binding to VE-cadherin, another pool of VE-PTP is associated with Tie2, the tyrosine kinase receptor present in the endothelial plasmalemma, and which functions to restrain Tie2 activity. On the basis of these observations, in Project 1 we will pursue the following Specific Aims: (i) we will determine the synergistic role of (a) HIF-dependent expression of VE-PTP as an adaptive mechanism promoting the stabilization of VE-cadherin at AJs, and (b) HIF-dependent activation of Rac1 and Cdc42 at AJs in sealing and strengthening the AJ barrier and thus restoring lung fluid balance; (ii) we will determine the role of VE-PTP interaction with Tie2 in regulating the repair of AJs through the activation of Tie2 signaling and the translocation of VE-PTP to VE-cadherin, and resulting in VE-cadherin stabilization; and (iii) we will determine the therapeutic value of (a) blocking prolyl hydroxylases (PHDs) to activate HIF-mediated transcription of VE-PTP, and (b) inhibiting Tie2 interaction with VE-PTP in restoring lung vascular barrier function and fluid balance in models of inflammatory lung injury. We will apply a rigorous multidisciplinary approach to define the signaling mechanisms activated by VE-PTP interaction with VE-cadherin in restoring the integrity of lung endothelial barrier, with the intent of identifying new targets to normalize lung fluid balance and the course of inflammatory lung injury.

Public Health Relevance

VE-PTP interaction with VE-cadherin at adherens junctions (AJs) of the endothelium is required for AJs re- annealing. We will study the function of VE-PTP that may have an essential role in the restoration of lung endothelial junctional barrier and fluid balance after inflammatory injury.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
2P01HL060678-16A1
Application #
9151430
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Xiao, Lei
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Di, Anke; Mehta, Dolly; Malik, Asrar B (2016) ROS-activated calcium signaling mechanisms regulating endothelial barrier function. Cell Calcium 60:163-71
Tauseef, Mohammad; Farazuddin, Mohammad; Sukriti, Sukriti et al. (2016) Transient receptor potential channel 1 maintains adherens junction plasticity by suppressing sphingosine kinase 1 expression to induce endothelial hyperpermeability. FASEB J 30:102-10
Gong, Haixia; An, Shejuan; Sassmann, Antonia et al. (2016) PAR1 Scaffolds TGFβRII to Downregulate TGF-β Signaling and Activate ESC Differentiation to Endothelial Cells. Stem Cell Reports 7:1050-1058
Rajput, Charu; Tauseef, Mohammad; Farazuddin, Mohammad et al. (2016) MicroRNA-150 Suppression of Angiopoetin-2 Generation and Signaling Is Crucial for Resolving Vascular Injury. Arterioscler Thromb Vasc Biol 36:380-8
Ebenezer, David L; Fu, Panfeng; Suryadevara, Vidyani et al. (2016) Epigenetic regulation of pro-inflammatory cytokine secretion by sphingosine 1-phosphate (S1P) in acute lung injury: Role of S1P lyase. Adv Biol Regul :
Zimnicka, Adriana M; Husain, Yawer S; Shajahan, Ayesha N et al. (2016) Src-dependent phosphorylation of caveolin-1 Tyr-14 promotes swelling and release of caveolae. Mol Biol Cell 27:2090-106
Jiang, Ying; Sverdlov, Maria S; Toth, Peter T et al. (2016) Phosphatidic Acid Produced by RalA-activated PLD2 Stimulates Caveolae-mediated Endocytosis and Trafficking in Endothelial Cells. J Biol Chem 291:20729-38
Liu, Yuru; Kumar, Varsha Suresh; Zhang, Wei et al. (2015) Activation of type II cells into regenerative stem cell antigen-1(+) cells during alveolar repair. Am J Respir Cell Mol Biol 53:113-24
Geyer, Melissa; Huang, Fei; Sun, Ying et al. (2015) Microtubule-Associated Protein EB3 Regulates IP3 Receptor Clustering and Ca(2+) Signaling in Endothelial Cells. Cell Rep 12:79-89
Zhang, Xianming; Brovkovych, Viktor; Zhang, Yongkang et al. (2015) Downregulation of kinin B1 receptor function by B2 receptor heterodimerization and signaling. Cell Signal 27:90-103

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