Abstract 16854: Multifunctional Regulation of Angiogenesis by High Density Lipoproteins
Aims: High density lipoproteins (HDL) exert anti-inflammatory effects and emerging evidence suggests that it may augment ischemia-mediated neovascularization. We hypothesized that HDL may conditionally regulate angiogenesis, depending on the pathophysiological context by: 1) inhibiting inflammation-induced angiogenesis, but also 2) enhancing ischemia-mediated angiogenesis.
Methods and Results: Intravenous apolipoprotein (apo) A-I attenuated neovascularization in the murine femoral collar model of inflammatory angiogenesis by 58±7.0% compared to saline infused C57B6 mice, p<0.01. Conversely, apoA-I augmented neovessel formation (75±22) and enhanced blood flow recovery (45±8.8) in the murine hind limb ischemia model (p<0.05). Reconstituted HDL (rHDL) was tested on key angiogenic cell functions in vitro. When exposed to two inflammatory stimuli: tumor necrosis factor-α (TNFα) and macrophage-conditioned media (MCM), rHDL inhibited human coronary artery endothelial cell migration (28±3.4% and 73±8.8%), proliferation (16±2.0% and 40±10%) and tubulogenesis on matrix gel (52±8.4% and 99±4.0%). In contrast, rHDL augmented hypoxia-stimulated migration (37±13%), proliferation (2-fold) and tubulogenesis (23±3.3%), all p<0.05. Western blot and RT-PCR analyses revealed the divergent actions of rHDL were associated with conditional regulation of hypoxia inducible factor-1α and vascular endothelial growth factor, which were significantly attenuated in response to TNFα (30±15% and 38±7.8%) and MCM (47±22% and 40±6.9%), but augmented by rHDL in hypoxia (40±12% and 53±28%). shRNA knock-down of scavenger receptor BI (SRBI) significantly abrogated the actions of rHDL in angiogenic functional assays, indicating that SRBI is a key mediator of rHDL activity. Moreover, augmentation of ischemia-driven neovascularization by apoA-I was abolished in ischemic hind limbs of SRBI KO mice.
Conclusions: HDL differentially regulates angiogenesis, characterized by suppression of inflammation-induced angiogenesis, and conversely, by enhancement of hypoxia-mediated angiogenesis. These actions are mediated, at least in part, by SRBI. These findings may have significant implications for therapeutic modulation of neovascularization.
- © 2013 by American Heart Association, Inc.