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Vascular calcification (VC) is a highly regulated process with many similarities to developmental osteogenesis. Key features include release of vascular smooth muscle cell (VSMC) derived exosomes and dysregulated expression of physiological inhibitors of calcification such as fetuin-A (1). In vitro, fetuin-A is internalised by VSMCs and loaded into these exosomes which is thought to be a physiological mechanism to inhibit calcification. However this process becomes overwhelmed by calcification-inducing stress resulting in the loss of fetuin-A from the exosomes, thereby rendering them mineralisation competent to form the nidus for calcification (2). In dialysis-dependent patients with chronic renal disease, lower levels of serum fetuin-A are associated with VC (3) and fetuin-A co-localises with calcified arteries (2) suggesting that a similar inhibitory mechanism exists as seen in vitro. However it is unknown if an exosome-fetuin mechanism exists in the general, non-renal failure, population. Determine if fetuin-A enriched VSMC exosomes are found in the human circulation and if they reflect calcification stress. Exosomes isolated from human whole blood by differential centrifugation were enriched with the exosomal marker CD63 and contained the VSMC-specific marker α-smooth muscle actin, as detected by Western Blot. Using Western blot, fetuin-A was also detected in VSMC exosomes isolated from patients with and without clinically confirmed VC, with an observation of lower levels of fetuin-A in subjects with VC. In a cohort (n=16) of patients with VC, we investigated the relationship between exosomal fetuin-A (as determined by ELISA), exosomal calcium (as determined by a cresolphthalein assay) and clinically quantified VC (computed tomography derived calcium score). Linear regression analysis showed a negative correlation between the exosomal fetuin-A:calcium ratio and calcium score [r2 = -0.65; p<0.05] (see figure 1). VSMC-derived exosomes are present in the human circulation and contain the calcification inhibitor fetuin-A. A negative correlation exists between VSMC exosomal fetuin-A and clinical calcification, confirming previous in vitro observations that fetuin-A enriched VSMC exosomes may inhibit VC and could serve as a clinical marker of VC in the general population. [ABSTRACT FROM AUTHOR]