@article{1d71f62cf4d9450a9d0880b6604a9a22,
title = "Exchange protein directly activated by cAMP plays a critical role in regulation of vascular fibrinolysis",
abstract = "Plasmin-mediated fibrinolysis at the surface of vascular endothelial cells (SVEC) plays a key role in maintaining vascular hemostasis, in which the cAMP pathway participates. After externalization to the SVEC, annexin A2 (ANXA2) serves as a platform for conversion of plasminogen to plasmin. Here we describe a regulatory role of the exchange protein directly activated by cAMP (EPAC) in ANXA2 externalization and vascular fibrinolysis. Knockout of EPAC1 in mice results in a decreased ANXA2 expression on the SVEC associated with increased fibrin deposition and fibrinolytic dysfunction. Reduced levels of EPAC1 are also found in endocardial tissues beneath atrial mural thrombi in patients. Notably, administration of recombinant ANXA2 ameliorates fibrinolytic dysfunction in the EPAC1-null mice. Mechanistically, EPAC1 regulates the SVEC plasminogen conversion depended on ANXA2. EPAC1 promotes tyrosine-23 phosphorylation of ANXA2, a prerequisite for its recruitment to the SVEC. Our data thus reveal a novel regulatory role for EPAC1 in vascular fibrinolysis.",
keywords = "Annexin A2, Atomic force microscopy, EPAC1, Thrombosis, Vascular endothelial fibrinolysis",
author = "Xi He and Aleksandra Drelich and Shangyi Yu and Qing Chang and Dejun Gong and Yixuan Zhou and Yue Qu and Yang Yuan and Zhengchen Su and Yuan Qiu and Shao-Jun Tang and Angelo Gaitas and Thomas Ksiazek and Zhiyun Xu and Jia Zhou and Zongdi Feng and Maki Wakamiya and Fanglin Lu and Bin Gong",
note = "Funding Information: We gratefully acknowledge Dr. Edward Nelson for his important contributions for establishing the capacity of the atomic force microscopy (AFM) system, data analysis, and critical review of the manuscript. We gratefully acknowledge Drs. David Walker and Kimberly Schuenke for their critical reviews and editing of the manuscript. We thank Drs. Katherine Hajjar, Vladimir Motin, Vsevolod Popov, and Paul Boor for input during the planning phases of the experiments. We thank Xiang Li for assistance during revision. This work was supported by NIH grant R01 AI121012 (B.G.), National Natural Science Foundation of China grant 81370265 (F.L.), and NIH grants R01NS079166 and R01NS095747 (S.J.T.). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding Information: We gratefully acknowledge Dr. Edward Nelson for his important contributions for establishing the capacity of the atomic force microscopy (AFM) system, data analysis, and critical review of the manuscript. We gratefully acknowledge Drs. David Walker and Kimberly Schuenke for their critical reviews and editing of the manuscript. We thank Drs. Katherine Hajjar, Vladimir Motin, Vsevolod Popov, and Paul Boor for input during the planning phases of the experiments. We thank Xiang Li for assistance during revision. This work was supported by NIH grant R01 AI121012 (B.G.), National Natural Science Foundation of China grant 81370265 (F.L.), and NIH grants R01NS079166 and R01NS095747 (S.J.T.). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2019",
year = "2019",
month = mar,
day = "15",
doi = "10.1016/j.lfs.2019.02.014",
language = "English (US)",
volume = "221",
pages = "1--12",
journal = "Life Sciences",
issn = "0024-3205",
publisher = "Elsevier Inc.",
}