Disordered neovascularization and impaired wound healing are important contributors to diabetic vascular complications. We recently showed that high-density lipoproteins (HDL) enhance ischemia-mediated neovascularization and mounting evidence suggests HDL have anti-diabetic properties. We therefore hypothesized that HDL rescue diabetes-impaired neovascularization. Streptozotocin-induced diabetic mice had reduced blood flow recovery and neovessel formation in a hindlimb ischemia model compared to non-diabetic mice. Reconstituted HDL (rHDL) infusions in diabetic mice restored blood flow recovery and capillary density to non-diabetic levels. Topical rHDL application rescued diabetes-impaired wound closure, wound angiogenesis and capillary density. In vitro, rHDL increased key mediators involved in HIF-1α stabilization including the PI3K/Akt pathway, Siah1 and Siah2, and suppressed the prolyl hydroxylases PHD2 and PHD3. rHDL rescued high glucose-induced impairment of tubulogenesis and VEGFA protein production, a finding associated with enhanced phosphorylation of pro-angiogenic mediators VEGF receptor 2 (VEGFR2) and eNOS. Siah1/2 siRNA knockdown confirmed the importance of HIF-1α stability in mediating rHDL action. Lentiviral shRNA knockdown of scavenger receptor-BI (SR-BI) in vitro and SR-BI-/- diabetic mice in vivo, attenuated rHDL rescue of diabetes-impaired angiogenesis, indicating a key role for SR-BI. These findings provide a greater understanding of the vascular biological effects of HDL, with potential therapeutic implications for diabetic vascular complications.
- Received December 8, 2015.
- Accepted May 17, 2016.
- © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.