VEGF-A165 induces human aortic smooth muscle cell migration by activating neuropilin-1-VEGFR1-PI3K axis.
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.
Banerjee
Snigdha
S
Stem Cell Research Laboratory, Cancer Research Unit, VA Medical Center, Kansas City, Missouri 64128, USA. sbanerjee@kumc.edu
Mehta
Smita
S
Haque
Inamul
I
Sengupta
Krishanu
K
Dhar
Kakali
K
Kambhampati
Suman
S
Van Veldhuizen
Peter J
PJ
Banerjee
Sushanta K
SK
D019138:Antibodies, Blocking / Q000494:pharmacology; D001011:Aorta / Q000737:chemistry / Q000166:cytology* / Q000502:physiology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D004357:Drug Synergism; D020868:Gene Silencing; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000166:cytology* / Q000502:physiology; D039942:Neuropilin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000502:physiology; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000502:physiology; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism* / Q000502:physiology
D019138:Antibodies, Blocking; D010446:Peptide Fragments; D020033:Protein Isoforms; D042461:Vascular Endothelial Growth Factor A; C511613:vascular endothelial growth factor A (138-165); D039942:Neuropilin-1; D019869:Phosphatidylinositol 3-Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1; D051058:Oncogene Protein v-akt