Increased Lymphangiogenesis and Lymphangiogenic Growth Factor Expression in Perivascular Adipose Tissue of Patients with Coronary Artery Disease
Increased Lymphangiogenesis and Lymphangiogenic Growth Factor Expression in Perivascular Adipose Tissue of Patients with Coronary Artery Disease
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DOI：
10.3390/jcm8071000
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发表时间：
2019-07-01
影响因子：
3.9
通讯作者：
Schaefer, Katrin
中科院分区：
文献类型：
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作者：
Drosos, Ioannis;Pavlaki, Maria;Schaefer, Katrin
实验和人体尸检研究已将外膜淋巴管生成与动脉粥样硬化联系起来。缺乏对冠状动脉疾病患者血管周围淋巴管生成的分析。在这里，我们检查了心脏周围血管周围脂肪组织 (PVAT) (C-PVAT) 中的淋巴管生成及其潜在调节因子，并将其与乳内动脉的 PVAT (IMA-PVAT) 进行了比较。包括 46 名接受冠状动脉搭桥手术的患者。使用组织学、免疫组织化学、实时 PCR 和使用细胞因子阵列的 PVAT 条件培养基对围手术期收集的 C-PVAT 和 IMA-PVAT 进行分析。 C-PVAT 表现出 PECAM-1（血小板内皮细胞粘附分子 1）阳性血管密度增加。 C-PVAT 中表达淋巴管内皮透明质酸受体 1 或足足蛋白的淋巴管数量也有所增加，并与较高的炎症细胞数量、细胞间粘附分子 1 (ICAM1) 表达增加和纤维化相关。与 IMA-PVAT 相比，C-PVAT 中观察到淋巴管生成调节因子的表达显着升高，例如血管内皮生长因子 (VEGF)-C、VEGF-D 和 VEGF 受体 3。细胞因子阵列鉴定出血管生成素-2 在 C-PVAT 中比 IMA-PVAT 中表达更高。研究结果在组织学和 mRNA 水平上得到了证实。用重组血管生成素-2 与 VEGF-C 联合刺激人淋巴管内皮细胞可增强芽形成。我们的研究表明，与围绕未患病血管的 PVAT 相比，动脉粥样硬化动脉周围的 PVAT 表现出更广泛的淋巴管生成、炎症和纤维化，这可能是由于局部血管生成素-2、VEGF-C 和 VEGF-D 过度表达所致。
Experimental and human autopsy studies have associated adventitial lymphangiogenesis with atherosclerosis. An analysis of perivascular lymphangiogenesis in patients with coronary artery disease is lacking. Here, we examined lymphangiogenesis and its potential regulators in perivascular adipose tissue (PVAT) surrounding the heart (C-PVAT) and compared it with PVAT of the internal mammary artery (IMA-PVAT). Forty-six patients undergoing coronary artery bypass graft surgery were included. Perioperatively collected C-PVAT and IMA-PVAT were analyzed using histology, immunohistochemistry, real time PCR, and PVAT-conditioned medium using cytokine arrays. C-PVAT exhibited increased PECAM-1 (platelet endothelial cell adhesion molecule 1)-positive vessel density. The number of lymphatic vessels expressing lymphatic vessel endothelial hyaluronan receptor-1 or podoplanin was also elevated in C-PVAT and associated with higher inflammatory cell numbers, increased intercellular adhesion molecule 1 (ICAM1) expression, and fibrosis. Significantly higher expression of regulators of lymphangiogenesis such as vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF receptor-3 was observed in C-PVAT compared to IMA-PVAT. Cytokine arrays identified angiopoietin-2 as more highly expressed in C-PVAT vs. IMA-PVAT. Findings were confirmed histologically and at the mRNA level. Stimulation of human lymphatic endothelial cells with recombinant angiopoietin-2 in combination with VEGF-C enhanced sprout formation. Our study shows that PVAT surrounding atherosclerotic arteries exhibits more extensive lymphangiogenesis, inflammation, and fibrosis compared to PVAT surrounding a non-diseased vessel, possibly due to local angiopoietin-2, VEGF-C, and VEGF-D overexpression.