Drosos Ioannis, Pavlaki Maria, Ortega Carrillo Maria Del Pilar, Kourkouli Adriani, Buschmann Katja, Konstantinou Fotios, Gogiraju Rajinikanth, Bochenek Magdalena L, Chalikias Georgios, Tortopidis Christos, Vahl Christian F, Mikroulis Dimitrios, Tziakas Dimitrios, Münzel Thomas, Konstantinides Stavros, Schäfer Katrin
Center for Cardiology, Cardiology 1, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
Department of Cardiology, Democritus University of Thrace, 68100 Alexandroupolis, Greece.
J Clin Med. 2019 Jul 9;8(7):1000. doi: 10.3390/jcm8071000.
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.
实验研究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。目前缺乏对冠状动脉疾病患者血管周围淋巴管生成的分析。在此，我们研究了心脏周围血管周围脂肪组织（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血管周围脂肪组织（IMA-PVAT）进行比较。纳入了46例行冠状动脉旁路移植术的患者。对围手术期收集的C-PVAT和IMA-PVAT进行组织学、免疫组织化学、实时PCR分析，并使用细胞因子阵列分析PVAT条件培养基。C-PVAT中血小板内皮细胞黏附分子1（PECAM-1）阳性血管密度增加。表达淋巴管内皮透明质酸受体-1或足突蛋白的淋巴管数量在C-PVAT中也升高，并与更高的炎症细胞数量、细胞间黏附分子1（ICAM1）表达增加和纤维化相关。与IMA-PVAT相比，C-PVAT中淋巴管生成调节因子如血管内皮生长因子（VEGF）-C、VEGF-D和VEGF受体-3的表达明显更高。细胞因子阵列确定血管生成素-2在C-PVAT中比IMA-PVAT中表达更高。研究结果在组织学和mRNA水平得到证实。用重组血管生成素-2联合VEGF-C刺激人淋巴管内皮细胞可增强芽生形成。我们的研究表明，与未患病血管周围的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的过度表达。
