Abstract
Vascular smooth muscle cells (SMCs), one of the major cell types of the vascular wall, play a critical role in the process of angiogenesis under both physiological and pathophysiological conditions, including the cancer microenvironment. Previous studies have shown that VEGF-A 165 augments vascular SMC migration via VEGFR2 (KDR/Flk1) pathways. In this study, we found that VEGF-A 165 (recombinant protein or breast tumor cell-secreted) is also capable of inducing migration of VEGFR2-negative human aortic smooth muscle cells (hAOSMCs), and this induction is mediated through a molecular cross-talk of neuropilin-1 (NRP-1), VEGFR1 (Flt-1), and phosphoinositide 3-kinase (PI3K)/Akt signaling kinase. We found that VEGF-A 165 induces hAOSMC migration parallel with the induction of NRP-1 and VEGFR1 expressions and their associations along with the activation of PI3K/Akt. Neutralization of VEGF action by its antibody or inhibition of VEGF-induced PI3K/Akt kinase activation by wortmannin, a PI3K/Akt specific inhibitor, results in inhibition of VEGF-induced hAOSMC migration. Moreover, RNAi-mediated elimination of the NRP-1 expression or blocking of the activity of VEGFR1 by its antibody in hAOSMCs impairs the VEGF-A 165-induced migration of these cells as well as activation of PI3K/Akt kinase. Collectively, these results establish, for the first time, a mechanistic link among VEGF-A 165, NRP-1, VEGFR1, and PI3K/Akt in the regulation of migration of human vascular smooth muscle cells that eventually could be involved in the angiogenic switch.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Antibodies, Blocking / pharmacology
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Aorta / chemistry
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Aorta / cytology*
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Aorta / physiology
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Line
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Cell Line, Tumor
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Cell Movement / genetics
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Cell Movement / physiology*
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Drug Synergism
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Gene Silencing
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Humans
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Muscle, Smooth, Vascular / chemistry
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Muscle, Smooth, Vascular / cytology*
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Muscle, Smooth, Vascular / physiology
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Neuropilin-1 / antagonists & inhibitors
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Neuropilin-1 / biosynthesis
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Neuropilin-1 / metabolism*
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Neuropilin-1 / physiology
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Oncogene Protein v-akt / antagonists & inhibitors
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Oncogene Protein v-akt / physiology
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Peptide Fragments / biosynthesis
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Peptide Fragments / genetics
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Peptide Fragments / metabolism
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Peptide Fragments / physiology*
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphatidylinositol 3-Kinases / physiology
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Protein Isoforms / biosynthesis
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Protein Isoforms / genetics
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Protein Isoforms / physiology
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Signal Transduction / genetics
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Signal Transduction / immunology
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Vascular Endothelial Growth Factor A / biosynthesis
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
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Vascular Endothelial Growth Factor A / physiology*
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Vascular Endothelial Growth Factor Receptor-1 / antagonists & inhibitors
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Vascular Endothelial Growth Factor Receptor-1 / immunology
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Vascular Endothelial Growth Factor Receptor-1 / metabolism*
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Vascular Endothelial Growth Factor Receptor-1 / physiology
Substances
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Antibodies, Blocking
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Peptide Fragments
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Protein Isoforms
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A (138-165)
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Neuropilin-1
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Phosphatidylinositol 3-Kinases
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Vascular Endothelial Growth Factor Receptor-1
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Oncogene Protein v-akt