Vascular endothelial growth factor-D modulates oxidant-antioxidant balance of human vascular endothelial cells.

ABSTRACT

Vascular endothelial growth factor-D (VEGF-D) is an angiogenic and lymphangiogenic glycoprotein that facilitates tumour growth and distant organ metastasis. Our previous studies showed that VEGF-D stimulates the expression of proteins involved in cell-matrix interactions and promoting the migration of endothelial cells. In this study, we focused on the redox homoeostasis of endothelial cells, which is significantly altered in the process of tumour angiogenesis. Our analysis revealed up-regulated expression of proteins that form the antioxidant barrier of the cell in VEGF-D-treated human umbilical endothelial cells and increased production of reactive oxygen and nitrogen species in addition to a transient elevation in the total thiol group content. Despite a lack of changes in the total antioxidant capacity, modification of the antioxidant barrier induced by VEGF-D was sufficient to protect cells against the oxidative stress caused by hypochlorite and paraquat. These results suggest that exogenous stimulation of endothelial cells with VEGF-D induces an antioxidant response of cells that maintains the redox balance. Additionally, VEGF-D-induced changes in serine/threonine kinase mTOR shuttling between the cytosol and nucleus and its increased phosphorylation at Ser-2448, lead us to the conclusion that the observed shift in redox balance is regulated via mTOR kinase signalling.