Gremlin promotes vascular smooth muscle cell proliferation and migration

• Published in: Journal of molecular and cellular cardiology Vol. 44; no. 2; pp. 370 - 379
• Main Authors: Maciel, Thiago T, Melo, Rosilene S, Schor, Nestor, Campos, Alexandre H
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2008
• Subjects: Animals; Bone morphogenetic proteins; Bone Morphogenetic Proteins - metabolism; Bone Morphogenetic Proteins - pharmacology; Cardiovascular; Cell Movement; Cell Proliferation - drug effects; Cyclin-Dependent Kinase Inhibitor p27 - genetics; Cytokines; DNA - biosynthesis; Down-Regulation - drug effects; Gene Silencing - drug effects; Gremlin; Intercellular Signaling Peptides and Proteins - pharmacology; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - cytology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Phenotype; Proliferation; Proteins; Rats; Rats, Sprague-Dawley; Restenosis; Signal Transduction - drug effects; Tunica Intima - drug effects; Tunica Intima - pathology; Vascular smooth muscle cell; Restenosis; Bone morphogenetic proteins; Vascular smooth muscle cell; Gremlin; Proliferation
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2007.10.021

Abstract Recent reports highlight the importance of BMP in the vasculature. We investigated the expression pattern and role of the BMP antagonist gremlin in VSMC. We detected gremlin mRNA constitutive expression in adult and embryonic rat aortic VSMC, and in rat carotids. In vitro analysis demonstrated that angiotensin II, TGF-β1 and PDGF induced significant changes in gremlin mRNA expression. Gremlin stable overexpression in A7r5 cells blocked BMP signaling. BMP-induced reduction in VSMC DNA synthesis was markedly inhibited by gremlin overexpression. In fact, gremlin overexpression increased DNA synthesis and cell counts, and accelerated cell cycle progression of VSMC, through mechanisms that include p27kip1 down-regulation. Gremlin also led to marked increments in VSMC migration. In addition, gremlin gene silencing promoted a significant blockade on cell proliferation and migration. In vivo studies disclosed increased gremlin protein expression in the neointima of balloon-injured carotid arteries. In summary, the BMP antagonist gremlin is constitutively expressed in the normal vasculature. Gremlin induces VSMC proliferation and migration and is significantly regulated by growth factors and injury. We postulate that gremlin plays a part in the development of pathological phenotypic changes of adult VSMC.