Reconstituted high-density lipoproteins promote wound repair and blood flow recovery in response to ischemia in aged mice.
BACKGROUND
The average population age is increasing and the incidence of age-related vascular complications is rising in parallel. Impaired wound healing and disordered ischemia-mediated angiogenesis are key contributors to age-impaired vascular complications that can lead to amputation. High-density lipoproteins (HDL) have vasculo-protective properties and augment ischemia-driven angiogenesis in young animals. We aimed to determine the effect of reconstituted HDL (rHDL) on aged mice in a murine wound healing model and the hindlimb ischemia (HLI) model.


METHODS
Murine wound healing model-24-month-old aged mice received topical application of rHDL (50 μg/wound/day) or PBS (vehicle control) for 10 days following wounding. Murine HLI model-Femoral artery ligation was performed on 24-month-old mice. Mice received rHDL (40 mg/kg) or PBS, intravenously, on alternate days, 1 week pre-surgery and up to 21 days post ligation. For both models, blood flow perfusion was determined using laser Doppler perfusion imaging. Mice were sacrificed at 10 (wound healing) or 21 (HLI) days post-surgery and tissues were collected for histological and gene analyses.


RESULTS
Daily topical application of rHDL increased the rate of wound closure by Day 7 post-wounding (25 %, p < 0.05). Wound blood perfusion, a marker of angiogenesis, was elevated in rHDL treated wounds (Days 4-10 by 22-25 %, p < 0.05). In addition, rHDL increased wound capillary density by 52.6 %. In the HLI model, rHDL infusions augmented blood flow recovery in ischemic limbs (Day 18 by 50 % and Day 21 by 88 %, p < 0.05) and prevented tissue necrosis and toe loss. Assessment of capillary density in ischemic hindlimb sections found a 90 % increase in rHDL infused animals. In vitro studies in fibroblasts isolated from aged mice found that incubation with rHDL was able to significantly increase the key pro-angiogenic mediator vascular endothelial growth factor (VEGF) protein (25 %, p < 0.05).


CONCLUSIONS
rHDL can promote wound healing and wound angiogenesis, and blood flow recovery in response to ischemia in aged mice. Mechanistically, this is likely to be via an increase in VEGF. This highlights a potential role for HDL in the therapeutic modulation of age-impaired vascular complications.
The Heart Research Institute, 7 Eliza Street, Newtown, Sydney, 2042, Australia.
Tania
T
Tsatralis
The Heart Research Institute, 7 Eliza Street, Newtown, Sydney, 2042, Australia.|Sydney Medical School, University of Sydney, Camperdown, 2050, Sydney, Australia.
Anisyah
A
Ridiandries
The Heart Research Institute, 7 Eliza Street, Newtown, Sydney, 2042, Australia.|Sydney Medical School, University of Sydney, Camperdown, 2050, Sydney, Australia.
Stacy
S
Robertson
The Heart Research Institute, 7 Eliza Street, Newtown, Sydney, 2042, Australia.|Sydney Medical School, University of Sydney, Camperdown, 2050, Sydney, Australia.
Laura Z
LZ
Vanags
The Heart Research Institute, 7 Eliza Street, Newtown, Sydney, 2042, Australia.|Sydney Medical School, University of Sydney, Camperdown, 2050, Sydney, Australia.
Yuen Ting
YT
Lam
The Heart Research Institute, 7 Eliza Street, Newtown, Sydney, 2042, Australia.|Sydney Medical School, University of Sydney, Camperdown, 2050, Sydney, Australia.
Joanne T M
JT
Tan
The Heart Research Institute, 7 Eliza Street, Newtown, Sydney, 2042, Australia.|Sydney Medical School, University of Sydney, Camperdown, 2050, Sydney, Australia.|Department of Cardiology, Royal Prince Alfred Hospital, Camperdown, 2050, Sydney, Australia.
Martin K C
MK
Ng
The Heart Research Institute, 7 Eliza Street, Newtown, Sydney, 2042, Australia. bursillc@hri.org.au.|Sydney Medical School, University of Sydney, Camperdown, 2050, Sydney, Australia. bursillc@hri.org.au.
Christina A
CA
Bursill
D000375:Aging / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000187:drug effects / Q000473:pathology; D006614:Hindlimb / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008075:Lipoproteins, HDL / Q000008:administration & dosage* / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012039:Regional Blood Flow / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
D008075:Lipoproteins, HDL; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse
Aging; Angiogenesis; High-density lipoproteins; Vascular complications; Wound repair