RIPK3 modulates growth factor receptor expression in endothelial cells to support angiogenesis.
RIPK3 modulates growth factor receptor expression in endothelial cells to support angiogenesis.
复制标题
DOI：
10.1007/s10456-020-09763-5
复制
发表时间：
2021-08
期刊：
影响因子：
9.8
通讯作者：
Griffin CT
中科院分区：
文献类型：
--
作者：
Gao S;Griffin CT
受体相互作用蛋白激酶3(RIPK3)是一种多功能的细胞内蛋白，最初被认为是坏死性下垂程序性细胞死亡途径的重要组成部分。在血管发育过程中，RIPK3在非坏死性小鼠胚胎内皮细胞(ECs)中也有高表达，提示其在血管生成中具有潜在的作用。为了验证这一假设，我们产生了缺乏内皮RIPK3的小鼠，并在多个血管床中发现了非致命性的胚胎和围产期血管生成缺陷。我们的体外数据表明，RIPK3通过调节内皮细胞中生长因子受体的降解来支持血管生成。我们发现RIPK3与膜转运蛋白myoferlin相互作用，维持血管内皮生长因子受体2(VEGFR2)在血管内皮生长因子A(VEGFA)刺激下的表达。RIPK3基因敲除后减弱的Myoferlin的恢复，在VEGFA治疗后，挽救了RIPK3缺陷的ECs中VEGFR2表达的降低和血管的萌发。此外，我们发现RIPK3通过抑制ERK信号而调节与内皮识别相关的基因的表达，而不依赖于生长因子受体的周转。总之，我们的数据揭示了RIPK3在内皮细胞中出人意料的非坏死性作用，以及RIPK3促进体内发育血管生成的证据。
Receptor-interacting protein kinase 3 (RIPK3) is a multifunctional intracellular protein that was first recognized as an important component of the necroptosis programmed cell death pathway. RIPK3 is also highly expressed in non-necroptotic murine embryonic endothelial cells (ECs) during vascular development, indicating its potential contribution to angiogenesis. To test this hypothesis, we generated mice lacking endothelial RIPK3 and found non-lethal embryonic and perinatal angiogenesis defects in multiple vascular beds. Our in vitro data indicate that RIPK3 supports angiogenesis by regulating growth factor receptor degradation in ECs. We found that RIPK3 interacted with the membrane trafficking protein myoferlin to sustain expression of vascular endothelial growth factor receptor 2 (VEGFR2) in cultured ECs following vascular endothelial growth factor A (VEGFA) stimulation. Restoration of myoferlin, which was diminished after RIPK3 knockdown, rescued decreased VEGFR2 expression and vascular sprouting in RIPK3-deficient ECs after VEGFA treatment. In addition, we found that RIPK3 modulated expression of genes involved in endothelial identity by inhibiting ERK signaling independently of growth factor receptor turnover. Altogether, our data reveal unexpected non-necroptotic roles for RIPK3 in ECs and evidence that RIPK3 promotes developmental angiogenesis in vivo.
登录
查看更多内容
影响因子：
8.8
作者：
Dillon CP;Oberst A;Weinlich R;Janke LJ;Kang TB;Ben-Moshe T;Mak TW;Wallach D;Green DR
通讯作者：
Green DR
影响因子：
8.8
作者：
Dondelinger, Yves;Declercq, Wim;Vandenabeele, Peter
通讯作者：
Vandenabeele, Peter
影响因子：
4.8
作者：
Bernatchez, Pascal N.;Acevedo, Lisette;Sessa, William C.
通讯作者：
Sessa, William C.
影响因子：
64.5
作者：
Cho YS;Challa S;Moquin D;Genga R;Ray TD;Guildford M;Chan FK
通讯作者：
Chan FK
AutoTube：用于组织血管网络自动形态分析的新型软件。
影响因子：
9.8
作者：
Montoya-Zegarra JA;Russo E;Runge P;Jadhav M;Willrodt AH;Stoma S;Nørrelykke SF;Detmar M;Halin C
通讯作者：
Halin C