Geranylgeranyl pyrophosphate-mediated protein geranylgeranylation regulates endothelial cell proliferation and apoptosis during vasculogenesis in mouse embryo
Geranylgeranyl pyrophosphate-mediated protein geranylgeranylation regulates endothelial cell proliferation and apoptosis during vasculogenesis in mouse embryo
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香叶基香叶基焦磷酸介导的蛋白香叶基香叶基化调节小鼠胚胎血管生成过程中的内皮细胞增殖和凋亡
DOI：
10.1016/j.jgg.2021.03.009
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发表时间：
2021-04-20
影响因子：
5.9
通讯作者：
Li, Chaojun
中科院分区：
文献类型：
--
作者：
Chong, Danyang;Chen, Zhong;Li, Chaojun
在胚胎发育过程中，血管发育对于循环系统的建立是必不可少的，并且需要内皮细胞的增殖。然而，支撑监管机制的机制并未得到很好的理解。在这里，我们报道了香叶基香叶基焦磷酸(GGPP)，一种参与蛋白质香叶基香叶化的代谢产物，在胚胎血管发育中起着不可或缺的作用。GGPP是由香叶基香叶基焦磷酸合成酶(GGPPS)在甲氧丙酮酸途径中合成的。血管内皮细胞中Ggpps的选择性敲除导致血管发育异常和胚胎死亡，这是由于血管生成过程中内皮细胞增殖减少和凋亡增加所致。GGPP耗竭导致的蛋白香叶化缺陷抑制了RhoA的膜定位，增强了YAP的磷酸化，从而阻止了YAP进入细胞核，阻止了YAP靶基因的表达，这些基因与细胞增殖和抗凋亡过程有关。此外，辛伐他汀抑制甲氧戊酸途径可导致内皮细胞增殖缺陷和凋亡，而GGPP可改善这些缺陷。香叶醇(Geranylgeraniol，GGOH)是GGPP的前体，可减轻辛伐他汀对孕鼠胚胎血管发育的不利影响。这些结果表明，GGPP介导的蛋白Geranylgeranyation在胚胎血管发育过程中对内皮细胞的增殖和抗凋亡过程是必不可少的。版权所有(C)2021，中国科学院遗传与发育生物学研究所，中国遗传学会。爱思唯尔有限公司和科学出版社出版。版权所有。
Vascular development is essential for the establishment of the circulatory system during embryonic development and requires the proliferation of endothelial cells. However, the underpinning regulatory mechanisms are not well understood. Here, we report that geranylgeranyl pyrophosphate (GGPP), a metabolite involved in protein geranylgeranylation, plays an indispensable role in embryonic vascular development. GGPP is synthesized by geranylgeranyl pyrophosphate synthase (GGPPS) in the mevalonate pathway. The selective knockout of Ggpps in endothelial cells led to aberrant vascular development and embryonic lethality, resulting from the decreased proliferation and enhanced apoptosis of endothelial cells during vasculogenesis. The defect in protein geranylgeranylation induced by GGPP depletion inhibited the membrane localization of RhoA and enhanced yes-associated protein (YAP) phosphorylation, thereby prohibiting the entry of YAP into the nucleus and the expression of YAP target genes related to cell proliferation and the antiapoptosis process. Moreover, inhibition of the mevalonate pathway by simvastatin induced endothelial cell proliferation defects and apoptosis, which were ameliorated by GGPP. Geranylgeraniol (GGOH), a precursor of GGPP, ameliorated the harmful effects of simvastatin on vascular development of developing fetuses in pregnant mice. These results indicate that GGPP-mediated protein geranylgeranylation is essential for endothelial cell proliferation and the antiapoptosis process during embryonic vascular development. Copyright (C) 2021, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press. All rights reserved.