Tie1 ectodomain cleavage governs vascular responses to inflammatory stimulation but is dispensable for angiogenic signaling
Miki Kamiyama, Jingjing Shi, Lorna Rinck, Yanzhu Lin, Yifang Mao, Xiaowen Zhang, Ashik Ahmed Abdul Pari, Stephanie F. Preuss, Marlene Hoffarth, Gladys Hofsetz, Yuxi Di, Asmaa Zahran, Carleen Spegg, Maria Riedel, Donato Inverso, Roxana Ola, Junhao Hu, Kari Alitalo, Hellmut G. Augustin, Mahak Singhal
Miki Kamiyama, Jingjing Shi, Lorna Rinck, Yanzhu Lin, Yifang Mao, Xiaowen Zhang, Ashik Ahmed Abdul Pari, Stephanie F. Preuss, Marlene Hoffarth, Gladys Hofsetz, Yuxi Di, Asmaa Zahran, Carleen Spegg, Maria Riedel, Donato Inverso, Roxana Ola, Junhao Hu, Kari Alitalo, Hellmut G. Augustin, Mahak Singhal
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Research Letter Inflammation Vascular biology

Tie1 ectodomain cleavage governs vascular responses to inflammatory stimulation but is dispensable for angiogenic signaling

Abstract

Authors

Miki Kamiyama, Jingjing Shi, Lorna Rinck, Yanzhu Lin, Yifang Mao, Xiaowen Zhang, Ashik Ahmed Abdul Pari, Stephanie F. Preuss, Marlene Hoffarth, Gladys Hofsetz, Yuxi Di, Asmaa Zahran, Carleen Spegg, Maria Riedel, Donato Inverso, Roxana Ola, Junhao Hu, Kari Alitalo, Hellmut G. Augustin, Mahak Singhal

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Figure 1

Tie1 cleavage is dispensable for angiogenic responses but critical for inflammatory vascular responses.

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Tie1 cleavage is dispensable for angiogenic responses but critical for i...
(A) Genotype distribution of offspring from heterozygous breeders. T, targeted mutation. (B and C) Retinal analysis (P6): representative images (B) stained with EC marker IB4 (isolectin B4), tip cell marker ESM1 (endothelial cell–specific molecule 1), and/or pericyte marker NG2 (chondroitin sulfate proteoglycan 4) and quantification (C) of vascular outgrowth and pericyte coverage. Tie1-WT, n = 6; Tie1-CR, n = 18 mice. Scale bars: 100 μm. (D) Kaplan-Meier plot displaying lifespan of males. Tie1-WT, n = 14; Tie1-CR, n = 12 mice. (E) Representative images of Lewis Lung Carcinoma tumor vessels stained with EC marker CD31 and pericyte marker desmin. Scale bars: 50 μm. (F) Heatmap showing immune-responsive genes corresponding to the enriched gene set “TNF-alpha signaling via NF-κB.” (G) Top-ranked upstream regulators negatively predicted with the Ingenuity Pathway Analysis platform in Tie1-CR ECs. (H and I) IB (H) and quantification (I) of Tie1-ECD in plasma from Tie1-WT or Tie1-CR mice challenged with TNF-α or PBS for 6 hours. PBS, n = 4; TNF-α, n = 5 each. sTie1, soluble Tie1; FC, fold change. (J and K) Representative images (J) and FACS-based quantification (K) of Ly6G+ myeloid cells in lungs challenged with TNF-α or PBS for 6 hours. PBS, n = 3 (J) and 4 (K); TNF-α, n = 5 each (J and K). Scale bars: 20 μm. (L) Survival curves following LPS-induced endotoxemia. Males: Tie1-WT, n = 12; Tie1-CR, n = 9 mice. Females: Tie1-WT, n = 12; Tie1-CR, n = 11 mice. (M) Adhesion (left) and transendothelial migration (right) of U937 monocytes to Tie1-WT/Tie1-CR ECs. n = 4 (adhesion) and n = 5 (migration) replicates. (N) Representative images and the number of metastatic nodules in the lungs 2 weeks after i.v. injection of B16F10 cells. Tie1-WT, n = 11; Tie1-CR, n = 8 mice. Data are presented as mean ± SD (C, I, K, M, and N). ****P < 0.0001, ***P < 0.001, **P < 0.01, *P < 0.05. Mann-Whitney U test (C and N), 2-way ANOVA followed by Šidák’s multiple-comparison test (I, K, and M), and log-rank (Mantel-Cox) test (D and L).