title: Multifunctional regulation of angiogenesis by high-density lipoproteins.
abstract: OBJECTIVE
  High-density lipoproteins (HDL) exert striking anti-inflammatory effects and emerging evidence suggests that they may augment ischaemia-mediated neovascularization. We sought to determine whether HDL conditionally regulates angiogenesis, depending on the pathophysiological context by (i) inhibiting inflammation-induced angiogenesis, but also; (ii) enhancing ischaemia-mediated angiogenesis.
  
  
  RESULTS
  Intravenously delivered apolipoprotein (apo) A-I attenuated neovascularization in the murine femoral collar model of inflammation-induced angiogenesis, compared with phosphate-buffered saline infused C57BL6/J mice (58%), P < 0.05. Conversely, apoA-I delivery augmented neovessel formation (75%) and enhanced blood perfusion (45%) in the murine hindlimb ischaemia model, P < 0.05. Reconstituted HDL (rHDL) was tested on key angiogenic cell functions in vitro. rHDL inhibited human coronary artery endothelial cell migration (37.9 and 76.9%), proliferation (15.7 and 40.4%), and tubulogenesis on matrigel (52 and 98.7%) when exposed to two inflammatory stimuli: tumour necrosis factor-α (TNF-α) and macrophage-conditioned media (MCM). In contrast, rHDL significantly augmented hypoxia-stimulated migration (36.9%), proliferation (135%), and tubulogenesis (22.9%), P < 0.05. Western blot and RT-PCR analyses revealed that these divergent actions of rHDL were associated with conditional regulation of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and VEGF receptor 2, which were attenuated in response to TNF-α (40.4, 41.0, and 33.2%) and MCM (72.5, 30.7, and 69.5%), but augmented by rHDL in hypoxia (39.8, 152.6, and 15.7%%), all P < 0.05.
  
  
  CONCLUSIONS
  HDL differentially regulates angiogenesis dependent upon the pathophysiological setting, characterized by suppression of inflammation-associated angiogenesis, and conversely, by the enhancement of hypoxia-mediated angiogenesis. This has significant implications for therapeutic modulation of neovascularization.
authors.affiliation: The Heart Research Institute, 7 Eliza Street, Newtown, Sydney, NSW 2042, Australia.
authors.forename: Hamish C G
authors.initials: HC
authors.lastname: Prosser
authors.forename: Joanne T M
authors.initials: JT
authors.lastname: Tan
authors.forename: Louise L
authors.initials: LL
authors.lastname: Dunn
authors.forename: Sanjay
authors.initials: S
authors.lastname: Patel
authors.forename: Laura Z
authors.initials: LZ
authors.lastname: Vanags
authors.forename: Shisan
authors.initials: S
authors.lastname: Bao
authors.forename: Martin K C
authors.initials: MK
authors.lastname: Ng
authors.forename: Christina A
authors.initials: CA
authors.lastname: Bursill
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I; D002478:Cells, Cultured; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D011897:Random Allocation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D016632:Apolipoprotein A-I; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008075:Lipoproteins, HDL; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Angiogenesis; High-density lipoprotein; Inflammation; Ischaemia