VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells.
VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells.
复制标题
DOI：
10.1016/j.celrep.2021.109255
复制
发表时间：
2021-06-15
期刊：
影响因子：
8.8
通讯作者：
Yaniv K
中科院分区：
文献类型：
--
作者：
Jerafi-Vider A;Bassi I;Moshe N;Tevet Y;Hen G;Splittstoesser D;Shin M;Lawson ND;Yaniv K
新血管的形成需要增殖、分化和出芽之间的紧密同步。然而，这些过程是如何被差异激活的，通常是由相邻的内皮细胞（EC），仍然不清楚。在这里，我们确定细胞周期进程作为EC发芽和分化的调节器。使用转基因斑马鱼照明细胞周期阶段，我们表明，静脉和淋巴前体萌芽从主静脉专门在G1和揭示，细胞周期停滞诱导在这些EC过表达的p53和细胞周期蛋白依赖性激酶（CDK）抑制剂p27和p21。我们进一步证明，在体内，迫使G1期细胞周期停滞的结果增强血管发芽。从机制上讲，我们确定了促有丝分裂VEGFC/VEGFR 3/ERK轴作为EC细胞周期阻滞的直接诱导剂，并表征了使“发芽能力”EC的级联事件。总的来说，我们的研究结果揭示了一种机制，即有丝分裂原控制的细胞周期阻滞促进发芽，提出了关于使用细胞周期抑制剂在病理性血管生成和淋巴管生成的重要问题。内皮细胞在细胞周期的G1期从PCV出芽VEGFC/FLT 4/ERK诱导p53-、p21-和p27-介导的细胞周期停滞以使出芽成为可能强制的G1细胞周期停滞导致未分化EC的异位出芽Jerafi-Vider et al.报道了内皮细胞发芽的机制，其中促有丝分裂VEGFC/FLT 4/ERK信号通路诱导p53-、p21-和p27-介导的细胞周期停滞，赋予血管生成潜力。这些发现对于在病理性血管生成和淋巴管生成的情况下使用细胞周期抑制剂的假定短期效应具有重要意义。
The formation of new vessels requires a tight synchronization between proliferation, differentiation, and sprouting. However, how these processes are differentially activated, often by neighboring endothelial cells (ECs), remains unclear. Here, we identify cell cycle progression as a regulator of EC sprouting and differentiation. Using transgenic zebrafish illuminating cell cycle stages, we show that venous and lymphatic precursors sprout from the cardinal vein exclusively in G1 and reveal that cell-cycle arrest is induced in these ECs by overexpression of p53 and the cyclin-dependent kinase (CDK) inhibitors p27 and p21. We further demonstrate that, in vivo, forcing G1 cell-cycle arrest results in enhanced vascular sprouting. Mechanistically, we identify the mitogenic VEGFC/VEGFR3/ERK axis as a direct inducer of cell-cycle arrest in ECs and characterize the cascade of events that render “sprouting-competent” ECs. Overall, our results uncover a mechanism whereby mitogen-controlled cell-cycle arrest boosts sprouting, raising important questions about the use of cell cycle inhibitors in pathological angiogenesis and lymphangiogenesis. Endothelial cells sprout from the PCV in G1 phase of the cell cycle VEGFC/FLT4/ERK induce p53-, p21-, and p27-mediated cell-cycle arrest to enable sprouting Forced G1 cell-cycle arrest results in ectopic sprouting of undifferentiated ECs Jerafi-Vider et al. report a mechanism of endothelial cell sprouting, whereby the mitogenic VEGFC/FLT4/ERK signaling pathway induces p53-, p21-, and p27-mediated cell-cycle arrest, conferring angiogenic potential. These findings have important implications for the putative short-term effects of using cell cycle inhibitors in settings of pathological angiogenesis and lymphangiogenesis.
登录
查看更多内容
影响因子：
16.6
作者：
Fang JS;Coon BG;Gillis N;Chen Z;Qiu J;Chittenden TW;Burt JM;Schwartz MA;Hirschi KK
通讯作者：
Hirschi KK
影响因子：
2
作者：
Bouldin, Cortney M.;Kimelman, David
通讯作者：
Kimelman, David
影响因子：
4
作者：
Calder, Ashley;Roth-Albin, Ivana;Draper, Jonathan S.
通讯作者：
Draper, Jonathan S.
影响因子：
4.6
作者：
Jung, Hyun Min;Castranova, Daniel;Weinstein, Brant M.
通讯作者：
Weinstein, Brant M.
影响因子：
11.8
作者：
Kok, Fatma O.;Shin, Masahiro;Ni, Chih-Wen;Gupta, Ankit;Grosse, Ann S.;van Impel, Andreas;Kirchmaier, Bettina C.;Peterson-Maduro, Josi;Kourkoulis, George;Male, Ira;DeSantis, Dana F.;Sheppard-Tindell, Sarah;Ebarasi, Lwaki;Betsholtz, Christer;Schulte-Merker, Stefan;Wolfe, Scot A.;Lawson, Nathan D.
通讯作者：
Lawson, Nathan D.