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Introduction Systemic sclerosis (SSc) is a complex autoimmune disease with genetic and environmental determinants, characterized by vascular injury and fibrosis. A key feature of SSc-related fibrosis is extracellular matrix (ECM) dysregulation, resembling scarring seen in injured organ. Endothelial cell (EC) adhesion molecules, essential for vascular integrity, are negatively regulated by TGFB. Clinically, complications often begin in one organ and later in others, suggesting systemic mechanisms of disease progression. For instance, patients with digital-ulcers (DU) are at increased risk of developing interstitial lung disease (ILD). The mechanisms behind this systemic yet tissue-specific manifestation remain poorly understood. Extracellular vesicles (EVs), which mediate inter-organ communication, may contribute to this process. EVs carry cargo and surface adhesion molecules that influence tissue specificity. We hypothesize that EVs released by injured cells in one organ circulate systemically and contribute to pathology in distant organs, particularly when predisposing defects are presentWe investigate whether circulating EVs from SSc patients with DU and ILD (EV-DI) induce EC dysfunction and preferentially bind to fibrotic ECM, compared to EVs from patients without these complications (EV).Material and Methods EVs were isolated from serum of SSc patients with (EV-DI) and without (EV) DU and ILD using ExoQuick kit. EVs were characterized by Western-blot, electron microscopy, and Nanoparticle Tracking Analysis. Human umbilical vein ECs were exposed to EVs for 48 hours and assessed for proliferation and adhesion molecule expression (CD31, VE-cadherin). Fibrotic and control ECMs were generated by culturing dermal fibroblasts with or without TGF-beta, respectively, followed by decellularization. EVs binding to ECMs was quantified via Western-blot for the EV marker HSP70.Results EV-DI were enriched in TGFB (120% increase) compared to EV. EV-DI exposure significantly increased ECs proliferation (27% increase) and decreased CD31 and VE-cadherin expression (30–40% decrease). Proteins extracted from both ECM types lacked HSP70, confirming signal specificity from EVs. EV-DI bound significantly more than EV to fibrotic-like ECMs, and showed greater affinity for fibrotic versus control ECM (100% incerase).Conclusions EV-DI preferentially interact with fibrotic-ECM, modulate EC proliferation and disrupt adhesion, potentially impairing vascular integrity. These findings suggest pathological EVs enrichment in injured tissues such as inflamed lung, providing explanation for the systemic yet site-specific progression of SSc complications.