Reconstituted high-density lipoproteins promote wound repair and blood flow recovery in response to ischemia in aged mice

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.

Homo Sapiens (Hsa)-microRNA (miR)-6727-5p Contributes to the Impact of High-Density Lipoproteins on Fibroblast Wound Healing In Vitro

“…The first report that showed that high-density lipoproteins (HDL) can help to achieve this therapeutic goal came from Gordts et al (2014) [12], who demonstrated that topical administration of HDL gel improved delayed (splinted) wound healing in hypercholesterolaemic apolipoprotein (apo)E −/− mice. This finding resonates with reports that exposure to HDL can promote the proliferation of endothelial progenitor cells, aiding wound healing of the arterial wall in hypercholesterolaemic rats [13], and promote wound repair, rescue blood flow and promote neovessel formation due to ischaemia [14,15]; dysfunctional HDL, which arises in a number of disease states, impairs re-endothelialisation in vitro and in vivo [16][17][18][19]. Apolipoprotein (apo) A-I, the major protein component of HDL, and apoA-I mimetics can also promote arterial healing by reducing oxidative stress [20], and protect against impaired re-endothelialisation due to dysfunctional HDL [21], although it cannot entirely replicate the effect of HDL [22].…”

The regulation of miRNAs by reconstituted high-density lipoproteins in diabetes-impaired angiogenesis

“…Low HDL levels are an independent risk factor for the development of type 2 diabetes mellitus (T2DM) 16 and are associated with an increased risk of microvascular disease in T2DM patients 17 . We have previously shown that HDL augments ischaemia-driven angiogenesis 18 , 19 , an effect that is retained in aged mice 20 . We recently discovered that rHDL rescues diabetes-impaired angiogenesis through its ability to increase HIF-1α stability and VEGFA production 21 .…”

Exploring the Roles of CREBRF and TRIM2 in the Regulation of Angiogenesis by High-Density Lipoproteins

“…These effects were attenuated when rHDL-treated HCAECs were exposed to the inflammatory cytokine, tumor necrosis factor α (TNFα) [ 9 ], suggesting a dichotomous role for HDL in angiogenesis. In an in vivo setting, intravenous delivery of rHDL or apoA-I in murine models of hindlimb ischemia (HLI) resulted in accelerated recovery of blood perfusion and increased capillary density in the ischemic hindlimbs [ 9 , 11 , 12 , 13 ]. Similar results were seen in a rabbit model of HLI following treatment with des-fluoro-anacetrapib, an inhibitor of cholesteryl ester transfer protein (CETP) which raises HDL levels [ 14 ].…”