Premium
Utilizing mTOR inhibition to study the role of mTOR signal transduction in angiogenesis
Author(s) -
Ziegler Mary,
Hughes Christopher C.W.
Publication year - 2012
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.26.1_supplement.48.3
Subject(s) - angiogenesis , pi3k/akt/mtor pathway , microbiology and biotechnology , protein kinase b , signal transduction , cancer research , biology , regulator , phosphorylation , chemistry , biochemistry , gene
The growth and maintenance of normal blood vessels is disrupted in various disease processes, including malignant diseases in which tumor cells exploit the aberrant angiogenesis in order to grow and metastasize. Mammalian target of rapamycin (mTOR) is a downstream target of PI3K and is a central regulator of angiogenesis. We hypothesize that mTOR signal transduction is important in the molecular mechanism of angiogenesis. This study utilized a 3D in vitro fibrin bead model of angiogenesis and examined various mTOR inhibitors for their ability to block angiogenesis. In addition, protein and gene expression changes in human umbilical vein endothelial cells (HUVEC) grown in monolayer were examined. mTOR inhibition results in lumen loss in the 3D fibrin bead model of angiogenesis. HUVEC treated with mTOR inhibitors show loss of Akt phosphorylation at both S473 and T308 and the gene expression of VEGF and VEGFR2 are diminished. Claudin‐5 and VE‐Cadherin mRNA are reduced by rapamycin and one of the ATP‐competitive inhibitions. Claudin‐5 protein expression is inhibited by all of the mTOR inhibitors. These data suggest that mTOR plays a role in lumen formation and could be a regulator of endothelial cell junction formation. Further examination of these signaling pathways will contribute to our understanding of the molecular mechanisms underlying angiogenesis.