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The Effects of Hypercholesterolemia on Wound Healing and Angiogenesis
thesisposted on 01.12.2019 by Yedida Y Bogachkov
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Hypercholesterolemia, a nationwide problem, is excess cholesterol in the bloodstream, including both excess LDL and oxLDL. The true issue with hypercholesterolemia is the possible, adverse cardiovascular outcomes, such as myocardial infarction or stroke. This dissertation investigates how hypercholesterolemia affects endothelial cells and angiogenesis both in vitro and in vivo. These studies serve to show that exposing endothelial cells to hypercholesterolemic conditions, elevated levels of LDL similar to those seen in hypercholesterolemic patients, leads to cholesterol loading of endothelial cells. Additionally, this excess LDL leads to an increase in the lipid ordering of the cell membrane, as assessed by Laurdan 2-photon microscopy, which is consistent with an increase in the free cholesterol within the membrane bilayer. Notably, this effect is in direct opposition to that seen when cells are exposed to oxidized LDL, as seen in previously published work (Shentu et al. 2012) . These pathological levels of LDL also lead to an inhibition of endothelial proliferation, also opposite to the effects of oxidized LDL, which was previously shown to enhance endothelial proliferation (Zhang et al. 2017; Yu et al. 2011). When looking at in vivo angiogenesis, there was a difference seen in hypercholesterolemic mouse models. Matrigel plugs extracted from ApoE-/-, a mouse model of hypercholesterolemia, show a significant decrease in CD31/PECAM endothelial-specific staining, as compared to wild-type age and gender-matched controls, indicating decreased angiogenesis. Another mouse model of hypercholesterolemia, wild-type mice fed Western Diet for 24 weeks, did not show a significant anti-angiogenic effect. However, when that diet was extended to 40 weeks, there was strong angiogenesis inhibition. Finally, it was seen with a wound healing model that ApoE-/- mice show decreased angiogenesis during wound healing process following skin punch biopsies, as assayed by the level of CD31/PECAM expression and CD31/PECAM endothelial-specific staining. These same hypercholesterolemic mice show delayed wound closure, as well as an altered inflammation timeline, compared to their wild type control counterparts. Based upon both the current dissertation data and previous data (Oh et al. 2016), we suggest that excess LDL is anti-angiogenic, whereas excess oxLDL is pro-angiogenic. This dichotomy that exists between LDL and OxLDL may account for the controversial findings amongst the various angiogenesis models, and hypercholesterolemia’s effect upon them. Further studies can delve even further into this phenomenon and try to tease apart the mechanisms that may distinguish between the two effects in vivo.