Placental growth factor enhances angiogenesis in human intestinal microvascular endothelial cells via PI3K/Akt pathway: Potential implications of inflammation bowel disease

被引：34

作者：

Zhou, Yi ^{[1
]}

Tu, Chuantao ^{[1
]}

Zhao, Yuan ^{[1
]}

Liu, Hongchun ^{[1
]}

Zhang, Shuncai ^{[1
]}

机构：

[1] Fudan Univ, Dept Gastroenterol, Zhongshan Hosp, 180 Fenglin Rd, Shanghai 200032, Peoples R China

来源：

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS | 2016年 / 470卷 / 04期

基金：

中国国家自然科学基金;

关键词：

Inflammatory bowel disease; Angiogenesis; PIGF; HIMECs; PI3K/Akt pathway; EXPERIMENTAL COLITIS; CROHNS-DISEASE; PATHOGENESIS; PLGF; MIGRATION; CANCER; SERUM; VEGF;

D O I：

10.1016/j.bbrc.2016.01.073

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：

Background: Angiogenesis plays a major role in the pathogenesis of inflammatory bowel disease (IBD). Placental growth factor (PlGF) is a specific regulator of pathological angiogenesis and is upregulated in the sera of IBD patients. Therefore, the role of PlGF in IBD angiogenesis was investigated here using HIMECs. Methods: The expression of PlGF and its receptors in human intestinal microvascular endothelial cells (HIMECs) and inflamed mucosa of IBD patients were examined using quantitative PCR and western blot analysis and the role of PIGF in IBD HIMECs was further explored using small interfering RNA (siRNA). The induction of pro-inflammatory cytokine by PlGF in HIMECs was confirmed by ELISA. The capacity of PlGF to induce angiogenesis in HIMECs was tested through proliferation, cell-migration, matrigel tubule formation assays and its underlying signaling pathway were explored by western blot analysis of ERK1/2 and PI3K/Akt phosphorylation. Results: mRNA and protein expression of PIGF and its receptor NRP-1 were significantly increased in IBD HIMECs. Inflamed mucosa of IBD patients also displayed higher expression of PIGF. The production of IL-6 and TNF-alpha in culture supernatant of HIMECs treated with exogenous recombinant human PlGF-1 (rhPlGF-1) were increased. Furthermore, rhPlGF-1 significantly induced HIMECs migration and tube formation in a dose-dependent manner and knockdown of endogenous PlGF in IBD HIMECs using siRNA substantially reduced these angiogenesis activities. PIGF induced PI3K/Akt phosphorylation in HIMECs and pretreatment of PlGF-stimulated HIMECs with PI3K inhibitor (LY294002) significantly inhibited the PlGF-induced cell migration and tube formation. Conclusion: Our results demonstrated the pro-inflammatory and angiogenic effects of PIGF on HIMECs in IBD through activation of PI3K/Akt signaling pathway. PlGF/PI3K/Akt signaling may serve as a potential therapeutic target for IBD. (C) 2016 Elsevier Inc. All rights reserved.

引用

页码：967 / 974

页数：8

共 26 条

[1]

Bagli E, 2004, Autoimmun Rev, V3 Suppl 1, pS26

[2] Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions [J].

Carmeliet, P ;

Moons, L ;

Luttun, A ;

Vincenti, V ;

Compernolle, V ;

De Mol, M ;

Wu, Y ;

Bon, F ;

Devy, L ;

Beck, H ;

Scholz, D ;

Acker, T ;

DiPalma, T ;

Dewerchin, M ;

Noel, A ;

Stalmans, I ;

Barra, A ;

Blacher, S ;

Vandendriessche, T ;

Ponten, A ;

Eriksson, U ;

Plate, KH ;

Foidart, JM ;

Schaper, W ;

Charnock-Jones, DS ;

Hicklin, DJ ;

Herbert, JM ;

Collen, D ;

Persico, MG .

NATURE MEDICINE, 2001, 7 (05) :575-583

[3] KH902 suppresses high glucose-induced migration and sprouting of human retinal endothelial cells by blocking VEGF and PIGF [J].

Chen, X. ;

Li, J. ;

Li, M. ;

Zeng, M. ;

Li, T. ;

Xiao, W. ;

Li, J. ;

Wu, Q. ;

Ke, X. ;

Luo, D. ;

Tang, S. ;

Luo, Y. .

DIABETES OBESITY & METABOLISM, 2013, 15 (03) :224-233

[4] Differential angiogenic regulation of experimental colitis [J].

Chidlow, John H., Jr. ;

Langston, Will ;

Greer, James J. M. ;

Ostanin, Dmitry ;

Abdelbaqi, Maisoun ;

Houghton, Jeffery ;

Senthilkumar, Annamalai ;

Shukla, Deepti ;

Mazar, Andrew P. ;

Grisham, Matthew B. ;

Kevil, Christopher G. .

AMERICAN JOURNAL OF PATHOLOGY, 2006, 169 (06) :2014-2030

[5] Angiogenesis blockade as a new therapeutic approach to experimental colitis [J].

Danese, Silvio ;

Sans, Miquel ;

Spencer, David M. ;

Beck, Ivy ;

Donate, Fernando ;

Plunkett, Marian L. ;

de la Motte, Carol ;

Redline, Raymond ;

Shaw, David E. ;

Levine, Alan D. ;

Mazar, Andrew P. ;

Fiocchi, Claudio .

GUT, 2007, 56 (06) :855-862

[6] Angiogenesis as a novel component of inflammatory bowel disease pathogenesis [J].

Danese, Silvio ;

Sans, Miquel ;

De La Motte, Carol ;

Graziani, Cristina ;

West, Gail ;

Phillips, Manijeh H. ;

Pola, Roberto ;

Rutella, Sergio ;

Willis, Joe ;

Gasbarrini, Antonio ;

Fiocchi, Claudio .

GASTROENTEROLOGY, 2006, 130 (07) :2060-2073

[7] The discovery of placenta growth factor and its biological activity [J].

De Falco, Sandro .

EXPERIMENTAL AND MOLECULAR MEDICINE, 2012, 44 (01) :1-9

[8] FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? [J].

Fischer, Christian ;

Mazzone, Massimiliano ;

Jonckx, Bart ;

Carmeliet, Peter .

NATURE REVIEWS CANCER, 2008, 8 (12) :942-956

[9] Akt mediates cytoprotection of endothelial cells by vascular endothelial growth factor in an anchorage-dependent manner [J].

Fujio, Y ;

Walsh, K .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (23) :16349-16354

[10] Therapeutic DNA vaccination and RNA interference in inflammatory bowel disease [J].

Gardlik, Roman ;

Bartonova, Anastazie ;

Celec, Peter .

INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, 2013, 32 (02) :492-496

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