caa a22 4500 606177108 CHVBK 20210128100750.0 cr unu---uuuuu 210128e20150101xx s 000 0 eng 10.1007/s00018-014-1667-3 doi (NATIONALLICENCE)springer-10.1007/s00018-014-1667-3 ADAMTS13 and its variants promote angiogenesis via upregulation of VEGF and VEGFR2 [Elektronische Daten] [Manfai Lee, Justin Keener, Juan Xiao, X. Long Zheng, George Rodgers] Severe plasma ADAMTS13 deficiency results in the clinical disorder thrombotic thrombocytopenic purpura. However, other potential pathophysiological roles of ADAMTS13 in endothelial cell biology remain unexplored. The goals of this study were to understand the angiogenic pathways ADAMTS13 activates and to identify the important structural components of ADAMTS13 that stimulate angiogenesis. Incubation of human umbilical vein endothelial cells (HUVEC) with 150ng/mL (1nM) of recombinant human ADAMTS13 induced VEGF expression by 53% and increased VEGF mRNA by over sixfold, both within 10min; the measured VEGF levels steadily decreased over 2h, as shown by Western blot and ELISA. Phosphorylation of VEGFR2 was significantly enhanced in HUVEC after incubation with ADAMTS13 (1nM). Structure-function analysis showed that an ADAMTS13 variant containing thrombospondin type 1 (TSP1) 2-8 repeats (TSP1 2-8), TSP1 2-8 plus CUB domains (TSP1 2-8 plus CUB), or TSP1 5-8 repeats plus CUB domains (TSP1 5-8 plus CUB) increased HUVEC proliferation by 41-54% as compared to the EBM-2 controls. Chemotaxis assays further demonstrated that the TSP1 domains of ADAMTS13 increased HUVEC migration by 2.65-fold. Incubation of HUVEC with both ADAMTS13 variants containing TSP1 repeats and anti-VEGF IgG abrogated the enhanced effect of ADAMTS13 on proliferation, migration, and VEGFR2 phosphorylation. In conclusion, ADAMTS13-induced endothelial cell angiogenesis occurs via the upregulation of VEGF and phosphorylation of VEGFR2. This angiogenic activity depends on the C-terminal TSP1 repeats of ADAMTS13. Springer Basel, 2014 ADAMTS13 nationallicence VEGF nationallicence Angiogenesis nationallicence HUVEC nationallicence Proliferation nationallicence Migration nationallicence Lee Manfai Division of Hematology and Hematologic Malignancies, University of Utah Health Sciences Center, 30 N 1900 E Room 5C402, 84132, Salt Lake City, UT, USA aut Keener Justin Division of Hematology and Hematologic Malignancies, University of Utah Health Sciences Center, 30 N 1900 E Room 5C402, 84132, Salt Lake City, UT, USA aut Xiao Juan Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania, 19104, Philadelphia, PA, USA aut Long Zheng X. Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania, 19104, Philadelphia, PA, USA aut Rodgers George Division of Hematology and Hematologic Malignancies, University of Utah Health Sciences Center, 30 N 1900 E Room 5C402, 84132, Salt Lake City, UT, USA aut Cellular and Molecular Life Sciences Springer Basel 72/2(2015-01-01), 349-356 1420-682X 72:2<349 2015 72 18 https://doi.org/10.1007/s00018-014-1667-3 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-014-1667-3 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Lee Manfai Division of Hematology and Hematologic Malignancies, University of Utah Health Sciences Center, 30 N 1900 E Room 5C402, 84132, Salt Lake City, UT, USA aut NATIONALLICENCE 700 1- Keener Justin Division of Hematology and Hematologic Malignancies, University of Utah Health Sciences Center, 30 N 1900 E Room 5C402, 84132, Salt Lake City, UT, USA aut NATIONALLICENCE 700 1- Xiao Juan Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania, 19104, Philadelphia, PA, USA aut NATIONALLICENCE 700 1- Long Zheng X. Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania, 19104, Philadelphia, PA, USA aut NATIONALLICENCE 700 1- Rodgers George Division of Hematology and Hematologic Malignancies, University of Utah Health Sciences Center, 30 N 1900 E Room 5C402, 84132, Salt Lake City, UT, USA aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/2(2015-01-01), 349-356 1420-682X 72:2<349 2015 72 18