Figure 4.

The proangiogenic effects of HDL in endothelial cells. Following interaction with scavenger receptor (SR)-B1, HDL activates downstream PI3K/Akt signaling. This increases HIF-1α stabilization through an increase in the ubiquitin ligases Siah-1 and Siah-1, which inhibit the PHD proteins PHD-2 and PHD-4 that normally target HIF-1α for degradation. With increased HIF-1α stabilization, it allows for elevated levels of HIF-1α translocation to the nucleus. In the nucleus, HIF-1α binds to HIF response elements (HRE) in the promoter regions of proangiogenic genes, including VEGF-A, which increases their expression. This increases the interaction between VEGF-A and its receptor VEGFR2, leading to enhanced activation of ERK1/2 and p38 MAPK that promote endothelial cell migration and proliferation, respectively, and results in increased angiogenesis. PHD, prolyl hydroxylase domain; VEGFR2, vascular endothelial growth factor receptor 2. Color images are available online.