A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.
Research Unit of Medical Imaging, Physics and Technology, University of Oulu, Oulu, Finland.
Sci Rep. 2018 Nov 12;8(1):16709. doi: 10.1038/s41598-018-34770-4.
Heart has a wide lymphatic network but the importance of cardiac lymphatic system in heart diseases has remained unclear. Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) is a key molecule in the development and maintenance of cardiac lymphatic vessels. Here we characterized the role of VEGFR3 in healthy hearts and after myocardial infarction (MI) by using sVEGFR3 transgenic mice expressing a soluble decoy VEGFR3 under K14 promoter and Chy mice which have an inactivating mutation in the VEGFR3 gene. Cardiac lymphatic vessels were significantly dilated in the healthy hearts of sVEGFR3 mice when compared to controls. Lymphatic vessels formed large sheet-like structures in Chy mice. Attenuated VEGFR3 signaling led to a more severe MI predisposing to a significantly higher mortality in sVEGFR3 mice than in control mice. sVEGFR3 mice displayed intramyocardial hemorrhages in the infarcted area indicating hyperpermeability of the vasculature. Furthermore, novel MRI methods TRAFF2 and TRAFF4 and histological analysis revealed a modified structure of the fibrotic infarcted area in sVEGFR3 mice. In conclusion, the downregulation of VEGFR3 signaling modifies the structure of cardiac lymphatic network and causes vascular leakiness and increased mortality after MI.
心脏具有广泛的淋巴网络，但心脏淋巴系统在心脏病中的重要性仍不清楚。血管内皮生长因子受体 3（VEGFR3）是心脏淋巴管发育和维持的关键分子。在这里，我们通过使用在 K14 启动子下表达可溶性诱饵 VEGFR3 的 sVEGFR3 转基因小鼠和具有 VEGFR3 基因失活突变的 Chy 小鼠，来表征 VEGFR3 在健康心脏和心肌梗死（MI）后的作用。与对照组相比，sVEGFR3 小鼠的心脏淋巴管在健康心脏中明显扩张。淋巴管在 Chy 小鼠中形成大片状结构。VEGFR3 信号的减弱导致 MI 倾向增加，sVEGFR3 小鼠的死亡率明显高于对照组小鼠。sVEGFR3 小鼠在梗死区域显示出心肌内出血，表明血管通透性增加。此外，新型 MRI 方法 TRAFF2 和 TRAFF4 以及组织学分析显示，sVEGFR3 小鼠的纤维化梗死区域的结构发生了改变。总之，VEGFR3 信号的下调改变了心脏淋巴管网络的结构，并导致 MI 后血管渗漏和死亡率增加。
