Abstract 15000: VEGFR2 is activated by high-density lipoproteins and plays a key role in the proangiogenic action of HDL in ischemia

Carla M. Cannizzo, Aaron A. Adonopulos, Anisyah Ridiandries, Laura Z. Vanags, Sui Ching G. Yuen, Tania Tsatralis, Rodney Henriquez, Stacy Robertson, Martin K. C. Ng, Yuen Ting Lam, Christina A. Bursill, Joanne T. M. Tan

Research output: Contribution to conferenceAbstract

Abstract

ntroduction: High-density lipoproteins (HDL) are implicated in the augmentation of hypoxia-induced angiogenesis. We have previously shown that reconstituted HDL (rHDL) induces the key angiogenic growth factor vascular endothelial growth factor A (VEGFA) and total protein levels of its receptor, VEGFR2, in response to hypoxia. VEGFR2 activation via phosphorylation is the critical event for mediating the downstream signalling events that promote angiogenesis. This study aimed to determine if rHDL activates VEGFR2 phosphorylation, the signalling events downstream of VEGFR2 and the importance of VEGFR2 in the pro-angiogenic effects of rHDL in hypoxia.

Hypothesis: rHDL activates VEGFR2 phosphorylation and downstream signalling events. VEGFR2 is important in the pro-angiogenic effects of rHDL in hypoxia.

Methods and Results: In human coronary artery endothelial cells in vitro, rHDL increased the activation of VEGFR2 in hypoxia. Consistent with this, rHDL enhanced the phosphorylation of downstream angiogenic signalling proteins ERK1/2 and p38 MAPK. Incubation with a VEGFR2 neutralising antibody completely attenuated rHDL-induced augmentation of VEGFR2, ERK1/2 and p38 MAPK phosphorylation and ablated tubule formation in vitro. In the murine hindlimb ischemia model, rHDL infusions enhanced blood flow perfusion and augmented capillary and arteriolar density, compared to PBS infused controls. Infusion of a VEGFR2 neutralising antibody completely ablated these pro-angiogenic effects of rHDL. Circulating Sca1+/CXCR4+ angiogenic progenitor cells, important for ischemia-induced neovascularization, were higher in rHDL infused mice 3 days post-ischemic induction, but this did not occur in mice that also received the VEGFR2 neutralising antibody.

Conclusions: rHDL activates VEGFR2 and downstream angiogenic signalling events. VEGFR2 plays a key role in the pro-angiogenic effects of rHDL in hypoxia/ischemia. These findings have therapeutic implications for angiogenic diseases associated with an impaired response to tissue ischemia.
Original languageEnglish
Publication statusPublished or Issued - 14 Nov 2017

Keywords

  • angiogenesis
  • apoA-I
  • hypoxia

Cite this