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.
|Publication status||Published or Issued - 14 Nov 2017|