Abstract
BackgroundThe 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.MethodsMurine 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.ResultsDaily 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).ConclusionrHDL 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.
Highlights
The average population age is increasing and the incidence of age-related vascular complications is rising in parallel
Topical reconstituted HDL (rHDL) promotes wound closure and wound angiogenesis in aged mice We investigated the effect of topically applied rHDL in a murine model that mimics human wound repair in aged mice
Consistent with this, blood perfusion determined by laser Doppler imaging, as a marker of wound angiogenesis, was significantly elevated in rHDL treated a b
Summary
The average population age is increasing and the incidence of age-related vascular complications is rising in parallel. Aged individuals have higher mortality and increased rates of limb amputation as a result of acute limb ischemia [4] In these circumstances, aged patients and animal models are reported to exhibit reduced tissue production of vascular endothelial growth factor (VEGF) and decreased hypoxia inducible factor (HIF)-1α stability and activation [5, 6]. Whilst this provides functional and mechanistic evidence for age-impaired wound healing and ischemia-mediated angiogenesis, the key triggers for these events have not been entirely elucidated. Recent data indicate that processes fundamental to aging play pivotal roles in cardiovascular disease associated with advanced age [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
