VEGF-A165 induces human aortic smooth muscle cell migration by activating neuropilin-1-VEGFR1-PI3K axis

被引:47
作者
Banerjee, Snigdha [1 ]
Mehta, Smita [1 ]
Haque, Inamul [1 ]
Sengupta, Krishanu [1 ]
Dhar, Kakali [1 ]
Kambhampati, Suman [1 ]
Van Veldhuizen, Peter J. [1 ]
Banerjee, Sushanta K. [1 ,2 ]
机构
[1] Vet Adm Med Ctr, Stem Cell Res Lab, Canc Res Unit, Kansas City, MO 64128 USA
[2] Univ Kansas, Med Ctr, Div Hematol & Oncol, Dept Anat & Cell Biol,Dept Med, Kansas City, KS 66160 USA
关键词
D O I
10.1021/bi8000352
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-A165 (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-A165 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 VEGFR 1 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-A165, 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.
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页码:3345 / 3351
页数:7
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