PDGF-Induced Migration of Vascular Smooth Muscle Cells Is Inhibited by Heme Oxygenase-1 Via VEGFR2 Upregulation and Subsequent Assembly of Inactive VEGFR2/PDGFRβ Heterodimers

被引：39

作者：

Cheng, Caroline ^{[1
]}

Haasdijk, Remco A. ^{[1
]}

Tempel, Dennie ^{[1
]}

den Dekker, Wijnand K. ^{[1
]}

Chrifi, Ihsan ^{[1
]}

Blonden, Lau A. J. ^{[1
]}

van de Kamp, Esther H. M. ^{[1
]}

de Boer, M.

Burgisser, Petra E. ^{[1
]}

Noorderloos, Annemarie ^{[1
]}

Rens, Joost A. P. ^{[2
]}

ten Hagen, Timo L. M. ^{[2
]}

Duckers, Henricus J. ^{[1
]}

机构：

[1] Erasmus Univ, Med Ctr, Mol Cardiol Lab, Thoraxctr, NL-3015 GE Rotterdam, Netherlands

[2] Erasmus Univ, Med Ctr, Lab Expt Surg Oncol, Sect Surg Oncol,Dept Surg, NL-3015 GE Rotterdam, Netherlands

来源：

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY | 2012年 / 32卷 / 05期

关键词：

PDGF; heme oxygenase; migration; vascular smooth muscle cell; CARBON-MONOXIDE; GROWTH-FACTOR; PROLIFERATION; EXPRESSION; ADHESION; INJURY;

D O I：

10.1161/ATVBAHA.112.245530

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

Objective-In cardiovascular regulation, heme oxygenase-1 (HO-1) activity has been shown to inhibit vascular smooth muscle cell (VSMC) proliferation by promoting cell cycle arrest at the G1/S phase. However, the effect of HO-1 on VSMC migration remains unclear. We aim to elucidate the mechanism by which HO-1 regulates PDGFBB-induced VSMC migration. Methods and Results-Transduction of HO-1 cDNA adenoviral vector severely impeded human VSMC migration in a scratch, transmembrane, and directional migration assay in response to PDGFBB stimulation. Similarly, HO-1 overexpression in the remodeling process during murine retinal vasculature development attenuated VSMC coverage over the major arterial branches as compared with sham vector-transduced eyes. HO-1 expression in VSMCs significantly upregulated VEGFA and VEGFR2 expression, which subsequently promoted the formation of inactive PDGFR beta/VEGFR2 complexes. This compromised PDGFR. phosphorylation and impeded the downstream cascade of FAK-p38 signaling. siRNA-mediated silencing of VEGFA or VEGFR2 could reverse the inhibitory effect of HO-1 on VSMC migration. Conclusion-These findings identify a potent antimigratory function of HO-1 in VSMCs, a mechanism that involves VEGFA and VEGFR2 upregulation, followed by assembly of inactive VEGFR2/PDGFR beta complexes that attenuates effective PDGFR beta signaling. (Arterioscler Thromb Vasc Biol.2012;32:1289-1298.)

引用

页码：1289 / +

页数：21

共 25 条

[1]

Rapamycin modulates the eNOS vs. shear stress relationship [J].

Cheng, Caroline ;

Tempel, Dennie ;

Oostlander, Angela ;

Helderman, Frank ;

Gijsen, Frank ;

Wentzel, Jolanda ;

van Haperen, Rien ;

Haitsma, David B. ;

Serruys, Patrick W. ;

van der Steen, Anton F. W. ;

de Crom, Rini ;

Krams, Rob .

CARDIOVASCULAR RESEARCH, 2008, 78 (01) :123-129

[2]

Dendritic Cell Function in Transplantation Arteriosclerosis Is Regulated by Heme Oxygenase 1 [J].

Cheng, Caroline ;

Noorderloos, M. ;

van Deel, Elza D. ;

Tempel, Dennie ;

den Dekker, Wijnand ;

Wagtmans, Kim ;

Duncker, Dirk J. ;

Soares, Miguel P. ;

Laman, Jon D. ;

Duckers, Henricus J. .

CIRCULATION RESEARCH, 2010, 106 (10) :1656-1666

[3]

Heme Oxygenase 1 Determines Atherosclerotic Lesion Progression Into a Vulnerable Plaque [J].

Cheng, Caroline ;

Noordeloos, Annemarie M. ;

Jeney, Viktoria ;

Soares, Miguel P. ;

Moll, Frans ;

Pasterkamp, Gerard ;

Serruys, Patrick W. ;

Duckers, Henricus J. .

CIRCULATION, 2009, 119 (23) :3017-A9

[4]

Stromal cell-derived factor 1 promotes angiogenesis via a heme oxygenase 1-dependent mechanism [J].

Deshane, Jessy ;

Chen, Sifeng ;

Caballero, Sergio ;

Grochot-Przeczek, Anna ;

Was, Halina ;

Calzi, Sergio Li ;

Lach, Radoslaw ;

Hock, Thomas D. ;

Chen, Bo ;

Hill-Kapturczak, Nathalie ;

Siegal, Gene P. ;

Dulak, Jozef ;

Jozkowicz, Alicja ;

Grant, Maria B. ;

Agarwal, Anupam .

JOURNAL OF EXPERIMENTAL MEDICINE, 2007, 204 (03) :605-618

[5]

Dorrell MI, 2002, INVEST OPHTH VIS SCI, V43, P3500

[6]

Heme oxygenase-1 protects against vascular constriction and proliferation [J].

Duckers, HJ ;

Boehm, M ;

True, AL ;

Yet, SF ;

San, H ;

Park, JL ;

Webb, RC ;

Lee, ME ;

Nabel, GJ ;

Nabel, EG .

NATURE MEDICINE, 2001, 7 (06) :693-698

[7]

Heme oxygenase activity modulates vascular endothelial growth factor synthesis in vascular smooth muscle cells [J].

Dulak, J ;

Józkowicz, A ;

Foresti, R ;

Kasza, A ;

Frick, M ;

Huk, I ;

Green, CJ ;

Pachinger, O ;

Weidinger, F ;

Motterlini, R .

ANTIOXIDANTS & REDOX SIGNALING, 2002, 4 (02) :229-240

[8]

Nitric oxide and angiogenic activity of endothelial cells:: direct or VEGF-dependent effect? [J].

Dulak, J ;

Józkowjcz, A .

CARDIOVASCULAR RESEARCH, 2002, 56 (03) :487-488

[9]

Heme oxygenase-1 and carbon monoxide in vascular pathobiology [J].

Dulak, Jozef ;

Deshane, Jessy ;

Jozkowicz, Alicja ;

Agarwal, Anupam .

CIRCULATION, 2008, 117 (02) :231-241

[10]

Gozzelino R, ANN REV PHARM TOXICO, V50, P323

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