The pro-inflammatory adipokine resistin induces a phenotypic switch of vascular smooth muscle cells (VSMC), a process decisive for atherosclerosis, including morphological changes, increased synthetic activity, proliferation and migration. The guanine-exchange factor ARNO (Cytohesin-2) has been shown to be important for morphological changes and migration of other cell types. In this study we dissected the role of ARNO in resistin induced VSMC phenotypic switching and signalling. Firstly, treatment with the cytohesin inhibitor Secin H3 prevented the resistin mediated induction of morphological changes in VSMC. Secondly, Secin H3 treatment as well as expression of an inactive ARNO (EK) reduced resistin induced VSMC synthetic activity, as assessed by matrix metalloproteinase 2 (MMP-2) expression, as well as the migration into a wound in vitro compared to ARNO WT expression. Thirdly, we found ARNO to influence MMP-2 expression and migration via activation of p38 MAPK and the JNK/AP-1 pathway. Interestingly, these processes were shown to be dependent on the binding of PIP 3 , as mutation of the ARNO PH-domain inhibited VSMC migration, MMP-2 expression as well as p38 MAPK and JNK signalling. Thus, we demonstrate that ARNO is an important link in resistin dependent cell signalling leading to morphological changes, MMP-2 production and migration of VSMC.Resistin is an adipokine, which is mainly expressed in peripheral blood mononuclear cells and macrophages 1,2 . Resistin levels were first found to be enhanced in serum of diabetic as well as obese mice 3 . In human, increased serum levels of resistin in diabetic and obese patients 4-6 was furthermore shown to correlate with the accumulation of metabolic syndrome factors in type 2 diabetes 7 as well as with other inflammatory diseases, such as atherosclerosis, rheumatic disease and sepsis 2,8 . As all these mentioned pathophysiological conditions are associated with vascular inflammation and thus an elevated risk of cardiovascular disease 9-11 , resistin has gained increasing interest as a potential biomarker 12 and target of therapeutic interventions 8 in the context of vascular inflammation and cardiovascular disease.Upon stimulation with inflammatory cytokines or adipokines, vascular smooth muscle cells (VSMC) undergo a phenotypic switch from a quiescent differentiated contractile phenotype to a proliferative, migratory and synthetic dedifferentiated one 13 . The phenotypic changes of VSMC contribute to the development of atherosclerosis 14 . During this process VSMC undergo morphological changes and downregulate proteins determining the contractile phenotype, such as smooth muscle (SM) α-Actin or SM myosin heavy chain, and instead upregulate genes such as metalloproteinases (MMP), characteristic for an increased synthetic activity, important for the invasive process, i.e. proliferation and migration 13 . VSMC migration is a complex process involving remodelling of the cytoskeleton, integrins regulating adhesion by interaction with extracellular matrix (ECM) proteins ...