Functional Study Of Geranylgeranyl Diphosphate Synthase GGPPS In Embryonic Developmental Angiogenesis

Blood vessels form the largest network in our body and constitute heart,the first organ in the embryo.The growth of blood vessels is essential for organ growth and repair.Dysregulation of this process known as angiogenesis contributes to massive inflammatory,immune malignant and ischaemic disorders.Three major processes by which blood vessels are formed go by the name of vasculogenesis,angiogenesis,and arteriogenesis.Molecular mechanisms study of angiogenesis and relative disease may not only provide insights into mechanisms for normal developmental cell fate decisions,but also lead to novel targeted therapeutic approaches for numerous diseases.During cardiovascular treatment,statins reduce the synthesis of cholesterol by inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase(HMG-CoA reductase)to improve endothelial cell activation.Relative article reported statins also interfered with angiogenesis by lowering FPP and GGPP content thus inhibit the geranylgeranylation and the farnesylation of small G protein who undergo isoprenylation modification,and reduce their activity.We focused on GGPPS(geranylgeranyl diphosphate synthase),the synthetase which catalyze the synthesis of GGPP,and the protein isoprenylation.We generated GGPPS tissue-specific knockout mice by cre-loxp system.Tie2-cre transgenic mice were mated to generate endothelial cell specific knockout mice.Paraffin section and immumofluorescence showed that the GGPPS endothelial cell specific knockout result in an early embryonic lethality at E10.5,embryo gradually absorbed by maternal uterus,embryonic vascular network structure in disorder,lack of large vascular branch and extra-embryonic blood vessels network is indistinct.At E9.5,GGPPS knockout mice have normal embryonic angiogenesis,but incomplete smooth muscle cells recruitment,and disordered structure of extra-embryonic blood vessels network structure.Through cell transfection technique,GGPPS knock out model was constructed in vitro.With immumofluorescence,MTT analysis and scratch test,the lack of GGPPS inhibit endothelial cell proliferation and vitality,but no significant effect on endothelial cell migration ability in HUVEC.The above results show that GGPPS endothelial cell specificity knockout caused embryonic vascular structures in disorder and extra-embryonic angiogenesis abnormally.We suspect that the lack of GGPPS is likely to affect in embryo,and endothelial cell proliferation process,resulting in an early embryonic lethality.It is confirmed that GGPPS plays an important role in the angiogenesis.And this study will offer a good model and new idea for clinical therapy.