Proteins of the NFAT family consist of four well characterized calcium (Ca2+)/calcineurin-sensitive transcription factors (NFATc1-c4), originally described as transcriptional activators of cytokine and immunoregulatory genes in T cells but now known to play a role in several cell types outside the immune system. NFAT signaling is required for normal heart valve formation and vascular patterning during embryogenesis, but the role of NFAT in the vasculature during adult life is less clear. Over the past decade we have focused on dissecting the Ca2+ signaling requirements for NFAT activation in the vasculature, on the identification of kinases that regulate the export of NFAT from the nucleus and on finding NFAT-target genes in this tissue. It is now also known that NFAT activation promotes migration and proliferation of cultured vascular smooth muscle cells (VSMC), and that blockade of NFAT signaling reduces neointima formation in a rat carotid artery injury model. Also, that NFAT activation enhances VSMC excitability and vasoconstriction and the expression of inflammatory markers (i.e.IL-6, tissue factor, COX-2, VCAM-1). NFAT and vascular complications of diabetes? Diabetes is a lifelong, incapacitating disease affecting 246 million people worldwide. Presently, it can neither be prevented nor cured and it is associated with devastating chronic macrovascular complications including coronary heart disease and stroke as well as microvascular disorders (nephropathy, retinopathy and neuropathy). The underlying pathogenesis is not clear, but hyperglycemia has been identified as an important risk factor. We have recently shown that modest elevations of extracellular glucose effectively activate NFAT in VSMCs of large arteries (aorta and cerebral) and in small (retinal) microvessels in mice, both ex vivo and in vivo. This effect involves the local release of extracellular nucleotides, such as UTP and UDP, acting on purinergic-2Y receptors, leading to increased [Ca2+]i and subsequent activation of calcineurin and NFATc3. In addition to promoting NFATc3 nuclear translocation, high glucose also reduces nuclear export of NFAT by inhibiting GSK-3β and JNK, providing additional mechanisms for glucose-induced NFAT activation. Once activated, NFAT promotes the expression of osteopontin (OPN). Diabetic mice showed increased expression of OPN in the ascending and thoracic aorta, vascular segments particularly prone to development of atherosclerosis and this was prevented by in vivo treatment with the NFAT inhibitor A-285222 or by lack of NFATc3 protein in arteries from NFATc3-/- mice. OPN is highly expressed in human atherosclerotic lesions and is not only a marker of inflammation but also an active player in the progression of atherosclerosis and restenosis. OPN expression is increased in the media of diabetic arteries, plasma levels of OPN have been shown to significantly correlate with progression of diabetic nephropathy and OPN levels in the vitreous are enhanced in patients with diabetic retinopathy. Thus, NFAT may act as a glucose-sensor in the vascular wall, translating changes in Ca2+ signals and kinase activity into changes in gene expression. We hypothesize that this signaling pathway represents an unexplored mechanism underlying diabetic vascular disease.