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

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.

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.

Combination therapies of growth factors, specifically SDF-1 and VEGF, might enhance angiogenesis more successfully than monotherapies under conditions of hypercholesterolaemia.