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Background and Aims The Beta Amyloid Precursor Cleaving Enzyme 1 (BACE1) has been extensively studied in Alzheimer’s Disease (AD) for its key role in the production of the beta amyloid protein (Aβ). However, recent studies have implicated BACE1 in the development of diet-induced vascular dysfunction, pointing to a novel target for diseases initiated by disruption of endothelial homeostasis (e.g.: hypertension). Uncontrolled pathological endothelial-to-mesenchymal transition (EndMT) has emerged as an early driver of pathological vascular remodelling and cardiovascular disease. Here we investigate how modulation of endothelial BACE1 levels and activity affects vascular stability through EndMT .Methods Combining transcriptomics and proteomics data, we identified the pathways most affected by BACE1 over-expression through pathway enrichment analysis. The role of BACE1 was further dissected using RNA interference, over-expression vectors and inhibitors in cell-based and mouse models of vascular dysfunction ( figure 1).Abstract BS34 Figure 1Results BACE1 over-expression in human umbilical vein endothelial cells (HUVEC) significantly increased by 2-fold (adjusted p-value < 0.05) the secretion (secretome) of activating and remodelling factors: MMP1/2, COL5A1/2, SPARC, PLAT, SERPINE1, TGFBI, HHIP ( figure 2A). When the proteins were analysed via pathway enrichment analysis, epithelial/endothelial-to-mesenchymal transition (EMT/EndMT) was significantly over-represented (p-value = 1.5 e-23) (figure 2B).Over-expression of BACE1 in human pulmonary artery endothelial cells (HPAEC) caused a significant increase in EndMT markers ACTA2, CCL2 and SNAI1/Snail (43%, 27% and 25% respectively) (figure 2C). Induction of EndMT in human umbilical cord endothelial cells (HUVEC) with 50 ng/mL TGFβ and 1 ng/mL IL-1β for 7 days caused a significant 5-fold increase in EndMT transcriptional regulator Snail. Co-treatment with BACE1 inhibitor M3 caused a significant reduction in Snail mRNA levels, comparable with control conditions (figure 2D). Finally, ApoE-/- mice were put on a western diet to induce vascular dysfunction. Collagen deposition was measured as a proxy for vascular stiffening and remodelling. Inhibition of BACE1 with M3 showed a significant reduction of 12% in the deposition of collagen around lung blood vessels compared to mice treated with vehicle (figure 2E-F).Abstract BS34 Figure 2Conclusions Taken together, these results suggest that BACE1 plays a role in the response and modulation of EndMT, potentially through regulation of the signalling downstream of TGFβ and IL-1β (i.e.: Snail) and the secretion of factors enhancing vascular remodelling. Since several BACE1 inhibitors have been developed and tested in the clinics, BACE1 represents an appealing drug target to counteract vascular dysfunction associated with EndMT-inducing stressors, opening novel therapeutic avenues for cardiovascular disease.