LDL induces cholesterol loading and inhibits endothelial proliferation and angiogenesis in Matrigels: correlation with impaired angiogenesis during wound healing
LDL induces cholesterol loading and inhibits endothelial proliferation and angiogenesis in Matrigels: correlation with impaired angiogenesis during wound healing
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DOI：
10.1152/ajpcell.00495.2018
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发表时间：
2020-04-01
影响因子：
5.5
通讯作者：
Levitan, Irena
中科院分区：
文献类型：
--
作者：
Bogachkov, Yedida Y.;Chen, Lin;Levitan, Irena
高胆固醇血症是不良心血管结局的主要危险因素，但其对血管生成和伤口愈合的影响尚不清楚。在这项研究中，使用质谱和laurdan双光子成像的组合，我们表明，低密度脂蛋白（LDL）的水平升高，如在高胆固醇血症患者中看到的，导致游离胆固醇和胆固醇酯的增加，以及增加内皮细胞膜的脂质顺序。值得注意的是，这些影响是不同的，相反的胆固醇负荷的缺乏和脂质秩序的破坏，在我们早期的研究中观察到的氧化低密度脂蛋白（oxLDL）。相同病理水平的LDL可显著抑制内皮细胞增殖，使细胞周期阻滞于G2/M期，而oxLDL可促进内皮细胞增殖，使细胞周期阻滞于S期。LDL而不是oxLDL抑制血管内皮生长因子受体-2的表达，同时增强血管内皮生长因子（VEGF）的表达。此外，我们发现，与年龄匹配的C57/BL 6野生型对照组相比，老年（8-10个月）高胆固醇血症载脂蛋白E缺陷（ApoE（-/-））小鼠在皮肤穿刺活检后显示伤口闭合延迟。伤口愈合的延迟与分化簇31血小板内皮细胞粘附分子内皮标记物的表达减少和伤口床内血管生成减少有关。此外，在ApoE（-/-）小鼠的Matrigel塞中和野生型小鼠中具有高水平LDL的Matrigel中观察到对生长因子VEGF和碱性成纤维细胞生长因子的内皮反应性降低。我们认为血浆高胆固醇血症是由于LDL水平升高而导致的抗血管生成作用。
Hypercholesterolemia is a major risk factor for adverse cardiovascular outcomes, but its effect on angiogenesis and wound healing is not well understood. In this study, using a combination of mass spectrometry and laurdan two-photon imaging, we show that elevated levels of low-density lipoprotein (LDL), like those seen in hypercholesterolemic patients, lead to an increase in both free cholesterol and cholesterol esters, as well as increase in lipid order of endothelial cell membranes. Notably, these effects are distinct and opposite to the lack of cholesterol loading and the disruption of lipid order observed in our earlier studies in response to oxidized LDL (oxLDL). The same pathological level of LDL leads to a significant inhibition of endothelial proliferation and cell cycle arrest in G2/M phase, whereas oxLDL enhances endothelial proliferation in S phase of the cycle. LDL but not oxLDL suppresses the expression of vascular endothelial growth factor receptor-2 while enhancing the expression of vascular endothelial growth factor (VEGF). Furthermore, we show that aged (8-10 mo) hypercholesterolemic apolipoprotein E-deficient (ApoE(-/-)) mice display delayed wound closure compared with age-matched C57/BL6 wild-type controls following a skin punch biopsy. The delay in wound healing is associated with a decreased expression of cluster of differentiation 31 platelet endothelial cell adhesion molecule endothelial marker and decreased angiogenesis within the wound bed. Furthermore, decreased endothelial responsiveness to the growth factors VEGF and basic fibroblast growth factor is observed in ApoE(-/-) mice in Matrigel plugs and in Matrigels with high levels of LDL in wild-type mice. We propose that plasma hypercholesterolemia is antiangiogenic due to elevated levels of LDL.