β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is a transmembrane aspartyl
protease notorious for its contribution to the aetiology of Alzheimer’s disease (AD). Notably, BACE1
is elevated in diseases displaying aberrant angiogenesis, including diabetes mellitus (DM), and is
implicated in VEGF Receptor 1 (VEGFR1) proteolysis (Devi et al., 2012 and Cai et al., 2012).
Therefore, we hypothesise that increased BACE1 activity in DM contributes to the altered
angiogenesis displayed in associated microvascular complications, including diabetic foot ulcers
(DFUs), and that BACE1 inhibitors may prevent such problems.
In vivo observations of the endothelium in the retina of BACE1-/- mice displayed a hyper-branching
phenotype in comparison to wild types. This was characterised by a decrease in radial outgrowth but
an increase in branch points, percentage vasculature area and quantity of filopodia. This finding was
further supported in vitro when exploiting the fibrin gel angiogenesis assay. Here, BACE1 inhibition
of human umbilical vein endothelial cells (HUVECs) exhibited an increase in sprouting (17 ± 3%,
P=<0.001) compared to controls. Lastly, an increase in the phosphorylation of eNOS at Serine 1177 in
HUVECs (+ 0.8 ± 0.2, P=0.05) and primary lung endothelial cells (PECs) (+ 0.2 ± 0.02), prior to VEGF
stimulations, provided a possible insight into the pro-angiogenic mechanisms of BACE1 inhibition.
Overall, our findings suggest that BACE1 inhibitors, previously trialled to treat AD, could be
repurposed to normalise angiogenesis in DM. This may reduce the risk of microvascular
complications from developing and prevent consequent amputations.
