MFAP4 Promotes Vascular Smooth Muscle Migration, Proliferation and Accelerates Neointima Formation

被引:77
|
作者
Schlosser, Anders [1 ,9 ]
Pilecki, Bartosz [1 ]
Hemstra, Line E. [1 ]
Kejling, Karin [1 ]
Kristmannsdottir, Gudlaug B. [1 ]
Wulf-Johansson, Helle [1 ]
Moeller, Jesper B. [1 ]
Fuchtbauer, Ernst-Martin [2 ]
Nielsen, Ole [3 ]
Kirketerp-Moller, Katrine [1 ]
Dubey, Lalit K. [1 ]
Hansen, Pernille B. L. [1 ]
Stubbe, Jane [1 ]
Wrede, Christoph [4 ,5 ,6 ]
Hegermann, Jan [4 ,5 ,6 ]
Ochs, Matthias [4 ,5 ,6 ]
Rathkolb, Birgit [7 ,8 ]
Schrewe, Anja [7 ]
Bekeredjian, Raffi [9 ]
Wolf, Eckhard [8 ]
Gailus-Durner, Valerie [7 ]
Fuchs, Helmut [7 ]
de Angelis, Martin Hrabe [7 ,10 ]
Lindholt, Jes S. [11 ,12 ]
Holmskov, Uffe [1 ]
Sorensen, Grith L. [1 ]
机构
[1] Univ Southern Denmark, Inst Mol Med, DK-5000 Odense, Denmark
[2] Aarhus Univ, Dept Mol Biol & Genet, Aarhus, Denmark
[3] Odense Univ Hosp, Dept Pathol, DK-5000 Odense, Denmark
[4] Hannover Med Sch, Inst Funct & Appl Anat, Hannover, Germany
[5] Biomed Res Endstage & Obstruct Lung Dis Hannover, Hannover, Germany
[6] REBIRTH Cluster Excellence, Hannover, Germany
[7] Helmholtz Zentrum Munchen, German Mouse Clin, Inst Expt Genet, German Res Ctr Environm Hlth, Munich, Germany
[8] Univ Munich, Inst Mol Anim Breeding & Biotechnol, Gene Ctr, Munich, Germany
[9] Heidelberg Univ, Div Cardiol, Dept Med 3, Heidelberg, Germany
[10] Tech Univ Munich, Chair Expt Genet, Ctr Life & Food Sci Weihenstephan, D-80290 Munich, Germany
[11] Viborg Hosp, Cardiovasc Res Unit, Viborg, Denmark
[12] Odense Univ Hosp, Dept Cardiothorac & Vasc Surg, Ctr Individualized Med Arterial Dis CIMA, DK-5000 Odense, Denmark
关键词
carotid stenosis; extracellular matrix proteins; hyperplasia; integrin alphaVbeta3; MFAP4; protein; mouse; muscle; smooth; vascular; MICROFIBRIL-ASSOCIATED GLYCOPROTEIN; FOCAL ADHESION KINASE; GENE-EXPRESSION; CELL-MIGRATION; IN-VITRO; INJURY; OSTEOPONTIN; HYPERPLASIA; INTEGRINS; MAGP-36;
D O I
10.1161/ATVBAHA.115.306672
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective Arterial injury stimulates remodeling responses that, when excessive, lead to stenosis. These responses are influenced by integrin signaling in vascular smooth muscle cells (VSMCs). Microfibrillar-associated protein 4 (MFAP4) is an integrin ligand localized to extracellular matrix fibers in the vascular wall. The role of MFAP4 in vascular biology is unknown. We aimed to test the hypothesis that MFAP4 would enhance integrin-dependent VSMC activation. Approach and Results We produced Mfap4-deficient (Mfap4(-/-)) mice and performed carotid artery ligation to explore the role of MFAP4 in vascular biology in vivo. Furthermore, we investigated the effects of MFAP4 in neointimal formation ex vivo and in primary VSMC and monocyte cultures in vitro. When challenged with carotid artery ligation, Mfap4(-/-) mice exhibited delayed neointimal formation, accompanied by early reduction in the number of proliferating medial and neointimal cells, as well as infiltrating leukocytes. Delayed neointimal formation was associated with decreased cross-sectional area of ligated Mfap4(-/-) carotid arteries resulting in lumen narrowing 28 days after ligation. MFAP4 blockade prohibited the formation of neointimal hyperplasia ex vivo. Moreover, we demonstrated that MFAP4 is a ligand for integrin (V3) and mediates VSMC phosphorylation of focal adhesion kinase, migration, and proliferation in vitro. MFAP4-dependent VSMC activation was reversible by treatment with MFAP4-blocking antibodies and inhibitors of focal adhesion kinase and downstream kinases. In addition, we showed that MFAP4 promotes monocyte chemotaxis in integrin (V3)-dependent manner. Conclusions MFAP4 regulates integrin (V3)-induced VSMC proliferation and migration, as well as monocyte chemotaxis, and accelerates neointimal hyperplasia after vascular injury.
引用
收藏
页码:122 / 133
页数:12
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