Peroxidases are heme-containing enzymes released by acti
vated immune cells at sites of inflammation. To-date their functional role in human health has mainly been limited to pro
viding a mechanism for oxidati
ve defence against in
vading bacteria and other pathogenic microorganisms. Our laboratory has recently identified a new functional role for peroxidase enzymes in stimulating fibroblast migration and collagen biosynthesis, offering a new insight into the causati
ve association between inflammation and the pro-fibrogenic e
vents that mediate tissue repair and regeneration. Peroxidases are found at ele
vated le
vels within and near blood
vessels howe
ver, their direct in
vol
vement in angiogenesis has ne
ver been reported. Here we report for the first time that myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are readily internalised by human umbilical
vein endothelial cells (HUVEC) where they promote cellular proliferation, migration, in
vasion, and stimulate angiogenesis both
in vitro and
in vivo. These pro-angiogenic effects were attenuated using the specific peroxidase inhibitor 4-ABAH, indicating the enzyme's catalytic acti
vity is essential in mediating this response. Mechanistically, we pro
vide e
vidence that MPO and EPO regulate endothelial FAK, Akt, p38 MAPK, ERK1/2 phosphorylation and stabilisation of HIF-2α, culminating in transcriptional regulation of key angiogenesis pathways.
These findings uncover for the first time an important and previously unsuspected role for peroxidases as drivers of angiogenesis, and suggest that peroxidase inhibitors may have therapeutic potential for the treatment of angiogenesis related diseases driven by inflammation.