Multifunctional regulation of angiogenesis by high-density lipoproteins

Hamish C G Prosser, Joanne T M Tan, Louise L. Dunn, Sanjay Patel, Laura Z. Vanags, Shisan Bao, Martin K C Ng, Christina A. Bursill

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

AimsHigh-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.Methods and resultsIntravenously 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- (TNF-) 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-1 (HIF-1), vascular endothelial growth factor (VEGF) and VEGF receptor 2, which were attenuated in response to TNF- (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.ConclusionHDL 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.

LanguageEnglish
Pages145-154
Number of pages10
JournalCardiovascular Research
Volume101
Issue number1
DOIs
Publication statusPublished - 1 Jan 2014

Keywords

  • Angiogenesis
  • High-density lipoprotein
  • Inflammation
  • Ischaemia

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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