Abstract
The MADS box transcription factor MEF2C has been detected by us to be upregulated by the angiogenic factors VEGF-A and bFGF in endothelial cells. We have here investigated its potential role for angiogenesis. MEF2C was surprisingly found to strongly inhibit angiogenic sprouting, whereas a dominant negative mutant rather induced sprouting. The factor mainly affected migratory processes of endothelial cells, but not proliferation. In gene profiling experiments we delineated the alpha-2-macroglobulin gene to be highly upregulated by MEF2C. Further data confirmed that MEF2C in endothelial cells indeed induces alpha-2-macroglobulin mRNA as well as the secretion of alpha-2-macroglobulin and that conditioned supernatants of cells overexpressing MEF2C inhibit sprouting. Alpha-2-macroglobulin mediates, at least to a large extent, the inhibitory effects of MEF2C as is shown by knockdown of alpha-2-macroglobulin mRNA by lentiviral shRNA expression which reduces the inhibitory effect. However, under hypoxic conditions the VEGF-A/bFGF-mediated upregulation of MEF2C is reduced and the production of alpha-2-macroglobulin largely abolished. Taken together, this suggests that the MEF2C/alpha-2-macroglobulin axis functions in endothelial cells as a negative feed-back mechanism that adapts sprouting activity to the oxygen concentration thus diminishing inappropriate and excess angiogenesis.
Highlights
Angiogenesis, the new formation of blood vessels by sprouting of vessel wall endothelial cells, is primarily induced by vascular endothelial growth factor A (VEGF-A) [1]
That the transcription factor myocyte enhancing factor 2C (MEF2C) is inducible by the pro-angiogenic mediators VEGF-A and, to some extent, by basic fibroblast growth factor (bFGF), but not by other inflammatory or more broadly active growth stimuli such as IL1 or EGF, respectively, implying a function during angiogenesis [6,20]
To delineate a potential function of MEF2C during angiogenesis, an in-gel spheroid sprouting assay was conducted with human umbilical vein endothelial cells (HUVEC) infected with an adenovirus driving overexpression of MEF2C
Summary
Angiogenesis, the new formation of blood vessels by sprouting of vessel wall endothelial cells, is primarily induced by vascular endothelial growth factor A (VEGF-A) [1]. VEGF-A/VEGFR2 signaling has been shown to strongly activate the PKC/MAPK and Ca++/ NFAT pathways via PLC-gamma as well as the PI3K/AKT pathway to induce migration, proliferation and survival [4,5] These initial signaling pathways triggered by VEGFA/VEGFR2 are well established, we are still devoid of detailed knowledge about the further downstream events leading to the consecutive upregulation of genes essential for the control of sprouting angiogenesis. Focusing on transcriptional regulators we have defined four transcription factors as the most strongly and upregulated by VEGF-A, and in part by basic fibroblast growth factor (bFGF), namely nuclear receptor subfamily 4, group A, member 2 (NR4A2), early growth response 3 (EGR3), H2.0-like homeobox (HLX) and myocyte enhancing factor 2C (MEF2C) These factors were not inducible by inflammatory mediators. In the case of the homeobox transcription factor HLX, we have been able to delineate an important function in the negative control of sprouting which is in part mediated via the HLX-mediated upregulation of the negative guidance receptor UNC5B under normoxic conditions [10]
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