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Increased Angiogenic Activity in tmTNF‐expressing Endothelial Cells Is Mediated by Matrix‐Metallo Proteinases via p38 MAPK Pathway
Author(s) -
Gangaraju Raja Shekhar,
Patterson Carolyn E,
Clauss Matthias A
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a635-b
Subject(s) - microbiology and biotechnology , angiogenesis , p38 mitogen activated protein kinases , matrix (chemical analysis) , chemistry , mapk/erk pathway , matrix metalloproteinase , cancer research , signal transduction , biology , biochemistry , chromatography
There is increasing evidence that chronic inflammation is tightly linked to diseases associated with endothelial dysfunction, including induction of aberrant angiogenesis. However, the direct involvement of activated endothelium has not been addressed in this context. Previously, using an uncleavable mutant of the transmembrane form of TNFα we have established models of stable TNFα expression in endothelial cells in vitro and in transgenic mice in vivo . Increased in vitro capillary sprout formation and increased neovascularization quantified by immunostaining with CD31 and CD34 in the in vivo Matrigel plug assay suggested an angiogenic role for endothelial tmTNF expression. Using pharmacological inhibition, we found that tmTNF‐cells demonstrated an angiogenic signaling switch from Erk‐1/2 to p38 MAPK compared to control cells when assessed in the in vitro angiogenesis assay independent of VEGF being added or not. Because matrix metallo‐proteinases are downstream of p38 MAPK, we tested a broad specific MMP‐inhibitor, GM6001, and observed decreased in vitro angiogenic activity in tmTNF cells but not in control cells. This finding suggests a possible novel and unique pathway for angiogenesis under chronic pro‐inflammatory conditions, which is mediated by the p38 MAPK and is independent of the growth factor related Erk‐1/2 signal transduction pathway. This work is supported by Indiana Center for Vascular Biology & Medicine.