Genetic dissection of tie pathway in mouse lymphatic maturation and valve development.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
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.).
Bin
B
Shen
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.).
Zhi
Z
Shang
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.).
Bo
B
Wang
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.).
Luqing
L
Zhang
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.).
Fei
F
Zhou
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.).
Taotao
T
Li
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.).
Man
M
Chu
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.).
Haijuan
H
Jiang
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.).
Ying
Y
Wang
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.).
Tong
T
Qiao
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.).
Jun
J
Zhang
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.).
Wei
W
Sun
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.).
Xiangqing
X
Kong
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.). yhe20005@gmail.com.
Yulong
Y
He
D042702:Angiopoietin-2 / Q000502:physiology; D000818:Animals; D042583:Lymphangiogenesis / Q000502:physiology*; D042601:Lymphatic Vessels / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D042810:Receptor, TIE-1 / Q000235:genetics / Q000502:physiology*; D042787:Receptor, TIE-2 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
D042702:Angiopoietin-2; D042810:Receptor, TIE-1; D042787:Receptor, TIE-2; C079086:Tek protein, mouse
Tie-1 receptor tyrosine kinase; Tie-2 receptor tyrosine kinase; knockout mice; lymphatic abnormality; lymphatic vessel; valve