Arterial injury stimulates remodeling responses. The regulation of these processes is important because excessive tissue formation leads to stenosis. Integrin signaling seems to be responsible for these processes. Microfibrillar-associated protein 4 (MFAP4) is an integrin ligand associated with extracellular matrix fibers in vascular walls and other tissues. It has been shown to play a role in remodeling-related diseases and resent in silico analysis predicted effects of MFAP4 deficiency on vascular physiology. The role of MFAP4 in vascular biology however is unknown. To investigate the biological effects of MFAP4 Anders Schlosser and colleagues generated Mfap4-/- mice.
While unchallenged Mfap4-/- mice did not show obvious differences compared to wild-type controls besides increased collagen fibril thickness in the arterial adventitia, significant effects were observed on remodeling processes after ligation-induced arterial injury. Mutant animals showed two weeks after injury induction a decreased vessel area and delayed neointima formation resulting in significant lumen narrowing four weeks after ligation.
In vitro analyses revealed that Mfap4 promotes vascular smooth muscle cell (VSCM) proliferation, adhesion and migration via integrin αVβ3 binding, which are essential events in neointima formation. Mfap4 deficiency abolished these processes and also diminished monocyte chemotaxis and inhibited fokal adhesion kinase (FAK) phosphorylation, a potential mechanism underlying MFAP4-mediated VSCM activation.
These observations demonstrate that MFAP4, a new player in cardiovascular pathologies, is redundant for normal cardiovascular development and arterial elastin assembly, but plays an important role in regenerative responses of the arterial wall.
Anders Schlosser, Bartosz Pilecki, Line E. Hemstra, Karin Kejling, Gudlaug B. Kristmannsdottir, Helle Wulf-Johansson, Jesper B. Moeller, Ernst-Martin Füchtbauer, Ole Nielsen, Katrine Kirketerp-Møller, Lalit K. Dubey, Pernille B.L. Hansen, Jane Stubbe, Christoph Wrede, Jan Hegermann, Matthias Ochs, Birgit Rathkolb, Anja Schrewe, Raffi Bekeredjian, Eckhard Wolf, Valérie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Jes S. Lindholt, Uffe Holmskov, Grith L. Sorensen. MFAP4 Promotes Vascular Smooth Muscle Migration, Proliferation and Accelerates Neointima Formation. Arterioscler Thromb Vasc Biol. 2016;36:122-133. DOI: 10.1161/ATVBAHA.115.306672.