SDF-1 restores angiogenesis synergistically with VEGF upon LDL exposure despite CXCR4 internalization and degradation

AIMS: Angiogenesis is compromised under conditions of hypercholesterolaemia. Since disturbed angiogenesis predisposes to ischaemic injuries, efforts have been made to promote angiogenesis by delivery of growth factors. How stromal cell-derived growth factor (SDF)-1 influences angiogenesis under conditions reflecting hypercholesterolaemia was unknown. METHODS AND RESULTS: We investigated the effects of SDF-1, administered alone or in combination with vascular endothelial growth factor (VEGF), on angiogenesis using proliferation, transwell migration, and Matrigel-based tube formation assays with human umbilical vein endothelial cells that were exposed to low-density lipoprotein (LDL). We observed that SDF-1 dose-dependently enhanced angiogenesis, but only partly reversed the LDL-mediated suppression of angiogenesis. Reduced abundance of SDF-1's receptor, CXCR4, was noted on the surface of LDL-exposed endothelial cells. In subcellular localization studies combined with pharmacological experiments, we showed that the loss of CXCR4 resulted from its internalization and degradation. SDF-1 synergistically increased angiogenesis when combined with VEGF. As a consequence, angiogenesis was fully restored. SDF-1 reduced oxidized LDL formation and increased the anti-oxidant capacity of endothelial cells, most strongly when administered together with VEGF. CONCLUSION: Combination therapies of growth factors, specifically SDF-1 and VEGF, might enhance angiogenesis more successfully than monotherapies under conditions of hypercholesterolaemia.