Zhong Chen
Shan Gua
Tongyu Zhang
Na Xu
Yue Zhao
Chaojun Li
Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and School of Medicine, Nanjing University, National Resource Center for Mutant Mice, Nanjing 210093, China
Funds: This work was supported by the National Natural Science Foundation of China (31530046 and 31771492), National Science and Technology Major Project (SQ2018YFC100242), Key R&D Program of Jiangsu Province (BE2017708), Fundamental Research Funds for the Central Universities (021414380469), and Nature Science Foundation of Jiangsu Province (BK20200061). The authors thank our laboratory members for their support regarding the technology and materials.
Received Date: 2020-10-25
Accepted Date:2021-03-16
Rev Recd Date:2021-03-14
Publish Date:2021-04-20
Abstract
Abstract
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.Keywords: GGPP,
Protein geranylgeranylation,
Endothelial cell,
Proliferation,
Apoptosis
PDF全文下载地址:
http://www.jgenetgenomics.org/article/exportPdf?id=40178a72-ab3c-4346-b63e-6f063b125247&language=en
