From the Laboratory of Vascular and Cancer Biology, Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, China (B.S., Z.S., L.Z., F.Z., T.L., M.C., H.J., Y.W., Y.H.); Laboratory of Vascular and Cancer Biology, MOE Key Laboratory for Model Animal and Disease Study, Model Animal Research Institute, Nanjing University, Nanjing, China (B.S., B.W., L.Z., F.Z., T.L., J.Z., W.S.); Department of Vascular Surgery, Nanjing Drum Tower Hospital, Nanjing, China (T.Q.); and Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China (W.S., X.K.).
Arterioscler Thromb Vasc Biol. 2014 Jun;34(6):1221-30. doi: 10.1161/ATVBAHA.113.302923. Epub 2014 Apr 24.
The genetic program underlying lymphatic development is still incompletely understood. This study aims to dissect the role of receptor tyrosine kinase with immunoglobulin-like and EGF (epidermal growth factor)-like domains 1 (Tie1) and Tie2 in lymphatic formation using genetically modified mouse models.
We generated conditional knockout mouse models targeting Tie1, Tie2, and angiopoietin-2 in this study. Tie1(ΔICD/ΔICD) mice, with its intracellular domain targeted, appeared normal at E10.5 but displayed subcutaneous edema by E13.5. Lymph sac formation occurred in Tie1(ΔICD/ΔICD) mice, but they had defects with the remodeling of primary lymphatic network to form collecting vessels and valvulogenesis. Consistently, induced deletion of Tie1-ICD postnatally using a ubiquitous Cre deleter led to abnormal lymphangiogenesis and valve formation in Tie1-ICD(iUCKO/-) mice. In comparison with the lymphatic phenotype of Tie1 mutants, we found that the diameter of lymphatic capillaries was significantly less in mice deficient of angiopoietin-2, besides the disruption of collecting lymphatic vessel formation as previously reported. There was also no lymphedema observed in Ang2(-/-) mice during embryonic development, which differs from that of Tie1(ΔICD/ΔICD) mice. We further investigated whether Tie1 exerted its function via Tie2 during lymphatic development. To our surprise, genetic deletion of Tie2 (Tie2(iUCKO/-)) in neonate mice did not affect lymphatic vessel growth and maturation.
In contrast to the important role of Tie2 in the regulation of blood vascular development, Tie1 is crucial in the process of lymphatic remodeling and maturation, which is independent of Tie2.
淋巴系统发育的遗传程序仍不完全清楚。本研究旨在利用基因修饰的小鼠模型剖析受体酪氨酸激酶免疫球蛋白样和表皮生长因子（EGF）样结构域 1（Tie1）和 Tie2 在淋巴管形成中的作用。
本研究中，我们生成了针对 Tie1、Tie2 和血管生成素-2 的条件性敲除小鼠模型。Tie1(ΔICD/ΔICD) 小鼠的细胞内结构域被靶向，在 E10.5 时表现正常，但在 E13.5 时出现皮下水肿。淋巴管囊形成发生在 Tie1(ΔICD/ΔICD) 小鼠中，但它们在初级淋巴管网络重塑形成收集管和瓣膜形成方面存在缺陷。同样，使用普遍的 Cre 缺失剂在出生后诱导 Tie1-ICD 的缺失导致 Tie1-ICD(iUCKO/-) 小鼠异常淋巴管生成和瓣膜形成。与 Tie1 突变体的淋巴管表型相比，我们发现除了先前报道的收集淋巴管形成中断外，血管生成素-2 缺失小鼠的淋巴管毛细血管直径明显较小。在胚胎发育过程中，Ang2(-/-) 小鼠也没有观察到淋巴水肿，这与 Tie1(ΔICD/ΔICD) 小鼠不同。我们进一步研究了 Tie1 是否在淋巴管发育过程中通过 Tie2 发挥作用。令我们惊讶的是，新生小鼠 Tie2（Tie2(iUCKO/-)）的遗传缺失并不影响淋巴管的生长和成熟。
与 Tie2 在调节血管发育中的重要作用相反，Tie1 在淋巴管重塑和成熟过程中至关重要，这独立于 Tie2。
