Local renin-angiotensin system regulates hypoxia-induced vascular endothelial growth factor synthesis in mesenchymal stem cells

The use of mesenchymal stem cell (MSC) transplantation for ischemic heart disease has been reported for several years. The main mechanisms responsible for the efficacy of this technique include the differentiation of MSCs into cardiomyocytes and endothelial cells, as well as paracrine effects. However, the differentiation rates of MSCs are very low, and the differentiated cells are not mature. In addition, MSCs undergo massive cell death within a few days after transplantation to the ischemic myocardium. Paracrine effects may thus play a major role in MSCs transplantation. Angiotensin II (Ang II) is known to be produced locally in the ischemic myocardium, but the effects of hypoxia on the local renin-angiotensin system (RAS) in MSCs, and the role of the RAS in hypoxia-induced vascular endothelial growth factor (VEGF) secretion remain unknown. In this study, we demonstrated that hypoxia stimulated the local RAS in MSCs, while pretreatment with the Ang II type 1 (AT1) receptor antagonist losartan reduced hypoxia-induced hypoxia-inducible factor 1α (HIF-1α) and VEGF production. The ERK1/2 inhibitor U0126 and the Akt inhibitor LY294002 also inhibited hypoxia-induced HIF-1α and VEGF production. Overall, these results indicate that the local RAS in MSCs regulates hypoxia-induced VEGF production through ERK1/2, Akt and HIF-1α pathways via the AT1 receptor.