Geranylgeranyl pyrophosphate-mediated protein geranylgeranylation regulates endothelial cell proliferation and apoptosis during vasculogenesis in mouse embryo.
Animals
Apoptosis
/ drug effects
Cell Differentiation
/ drug effects
Cell Proliferation
/ drug effects
Embryo, Mammalian
Embryonic Development
/ genetics
Endothelial Cells
/ drug effects
Farnesyltranstransferase
/ genetics
Female
Mice
Morphogenesis
/ genetics
Multienzyme Complexes
/ genetics
Polyisoprenyl Phosphates
/ metabolism
Pregnancy
Protein Prenylation
/ drug effects
YAP-Signaling Proteins
/ genetics
rhoA GTP-Binding Protein
/ genetics
Apoptosis
Endothelial cell
GGPP
Proliferation
Protein geranylgeranylation
Journal
Journal of genetics and genomics = Yi chuan xue bao
ISSN: 1673-8527
Titre abrégé: J Genet Genomics
Pays: China
ID NLM: 101304616
Informations de publication
Date de publication:
20 04 2021
20 04 2021
Historique:
received:
25
10
2020
revised:
14
03
2021
accepted:
16
03
2021
pubmed:
30
5
2021
medline:
19
1
2022
entrez:
29
5
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34049800
pii: S1673-8527(21)00089-8
doi: 10.1016/j.jgg.2021.03.009
pii:
doi:
Substances chimiques
Ggps1 protein, mouse
0
Multienzyme Complexes
0
Polyisoprenyl Phosphates
0
YAP-Signaling Proteins
0
Yap1 protein, mouse
0
Farnesyltranstransferase
EC 2.5.1.29
rhoA GTP-Binding Protein
EC 3.6.5.2
geranylgeranyl pyrophosphate
N21T0D88LX
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
300-311Informations de copyright
Copyright © 2021 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.