High-density lipoproteins rescue diabetes-impaired angiogenesis via scavenger receptor Class B Type i

Joanne T.M. Tan, Hamish C.G. Prosser, Louise L. Dunn, Laura Z. Vanags, Anisyah Ridiandries, Tania Tsatralis, Laura Leece, Zoë E. Clayton, Sui Ching G. Yuen, Stacy Robertson, Yuen Ting Lam, David S. Celermajer, Martin K.C. Ng, Christina A. Bursill

Research output: Contribution to journalArticle

Abstract

Disordered neovascularization and impaired wound healing are important contributors to diabetic vascular complications. We recently showed that high-density lipoproteins (HDLs) enhance ischemia-mediated neovascularization, and mounting evidence suggests HDL have antidiabetic 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 with nondiabetic mice. Reconstituted HDL (rHDL) infusions in diabetic mice restored blood flow recovery and capillary density to nondiabetic levels. Topical rHDL application rescued diabetes-impaired wound closure, wound angiogenesis, and capillary density. In vitro, rHDL increased keymediators involved in hypoxia-inducible factor-1α (HIF-1α) stabilization, including the phosphoinositide 3-kinase/Akt pathway, Siah1, and Siah2, and suppressed the prolyl hydroxylases (PHD) 2 and PHD3. rHDL rescued high glucose-induced impairment of tubulogenesis and vascular endothelial growth factor (VEGF) A protein production, a finding associated with enhanced phosphorylation of proangiogenic mediators VEGF receptor 2 and endothelial nitric oxide synthase. Siah1/2 small interfering RNA knockdown confirmed the importance of HIF-1a stability in mediating rHDL action. Lentiviral short hairpin RNA knockdown of scavenger receptor class B type I (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.

Original languageEnglish
Pages (from-to)3091-3103
Number of pages13
JournalDiabetes
Volume65
Issue number10
DOIs
Publication statusPublished - Oct 2016
Externally publishedYes

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  • Cite this

    Tan, J. T. M., Prosser, H. C. G., Dunn, L. L., Vanags, L. Z., Ridiandries, A., Tsatralis, T., Leece, L., Clayton, Z. E., Yuen, S. C. G., Robertson, S., Ting Lam, Y., Celermajer, D. S., Ng, M. K. C., & Bursill, C. A. (2016). High-density lipoproteins rescue diabetes-impaired angiogenesis via scavenger receptor Class B Type i. Diabetes, 65(10), 3091-3103. https://doi.org/10.2337/db15-1668