The multi-generation heredity trait of hypertension in human has been reported,but the molecular mechanisms underlying multi-generational inheritance of hypertension remain obscure.Recent evidence shows that prenatal inflammatory exposure(PIE)results in increased incidence of cardiovascular diseases,including hypertension.In this study we investigated whether and how PIE contributed to multi-generational inheritance of hypertension in rats.PIE was induced in pregnant rats by intraperitoneal injection of LPS or Poly(I∶C)either once on gestational day 10.5(transient stimulation,T)or three times on gestational day 8.5,10.5,and 12.5(persistent stimulation,P).Male offspring was chosen to study the paternal inheritance.We showed that PIE,irrespectively induced by LPS or Poly(I∶C)stimulation during pregnancy,resulted in multi-generational inheritance of significantly increased blood pressure in rat descendants,and that prenatal LPS exposure led to vascular remodeling and vasoconstrictor dysfunction in both thoracic aorta and superior mesenteric artery of adult F2 offspring.Furthermore,we revealed that PIE resulted in global alteration of DNA methylome in thoracic aorta of F2 offspring.Specifically,PIE led to the DNA hypomethylation of G beta gamma(Gβγ)signaling genes in both the F1 sperm and the F2 thoracic aorta,and activation of PI3K/Akt signaling was implicated in the pathologic changes and dysregulated vascular tone of aortic tissue in F2 LPS-P offspring.Our data demonstrate that PIE reprogrammed DNA methylome of cells from the germline/mature gametes contributes to the development of hypertension in F2 PIE offspring.This study broadens the current knowledge regarding the multi-generation effect of the cumulative early life environmental factors on the development of hypertension.

Xiao Guan;Guo-rong Dan;Yao Yang;Yan Ji;Wen-jing Lai;Fang-jie Wang;Meng Meng;Bang-hui Mo;Pei Huang;Ting-ting You;Ya-fei Deng;Liang Song;Wei Guo;Ping Yi;Jian-hua Yu;Yuan Gao;Wei-nian Shou;Bing-bo Chen;You-cai Deng;Xiao-hui Li

Institute of Materia Medica,College of Pharmacy,Army Medical University(Third Military Medical University),Chongqing 400038,China;Department of Obstetrics and Gynecology,The Third Affiliated Hospital of Chongqing Medical University,Chongqing 401120,China;The Ohio State University Comprehensive Cancer Center and the James Cancer Hospital,Columbus,OH 43210,USA;Department of Hematology&Hematopoietic Cell Transplantation,City of Hope National Medical Center and Beckman Research Institute,Duarte,CA 91010,USA;Southwest Hospital/Southwest Eye Hospital,Army Medical University(Third Military Medical University),Chongqing 400038,China;Herman B Wells Center for Pediatric Research,Department of Pediatrics,Indiana University School of Medicine,Indianapolis,IN 46202,USA;Laboratory Animal Center,Army Medical University(Third Military Medical University),Chongqing 400038,China

中国药理学报（英文版）

[1]Xiao Guan;Guo-rong Dan;Yao Yang;Yan Ji;Wen-jing Lai;Fang-jie Wang;Meng Meng;Bang-hui Mo;Pei Huang;Ting-ting You;Ya-fei Deng;Liang Song;Wei Guo;Ping Yi;Jian-hua Yu;Yuan Gao;Wei-nian Shou;Bing-bo Chen;You-cai Deng;Xiao-hui Li-.Prenatal inflammation exposure-programmed hypertension exhibits multi-generational inheritance via disrupting DNA methylome)[J].中国药理学报（英文版）,2022(06):1419-1429

irrespectively,vasoconstrictor

Prenatal,inflammation,exposure,hypertension,exhibits,multi,generational,inheritance,via,disrupting,methylome,heredity,trait,human,has,been,reported,molecular,mechanisms,underlying,remain,obscure,Recent,evidence,shows,that,prenatal,inflammatory,PIE,results,increased,incidence,cardiovascular,diseases,including,In,this,study,investigated,whether,contributed,rats,was,induced,pregnant,by,intraperitoneal,injection,LPS,Poly,either,once,gestational,day,transient,stimulation,three,times,persistent,Male,offspring,chosen,paternal,We,showed,during,pregnancy,resulted,significantly,blood,pressure,descendants,remodeling,dysfunction,both,thoracic,aorta,superior,mesenteric,artery,adult,F2,Furthermore,revealed,global,alteration,Specifically,hypomethylation,beta,gamma,signaling,genes,sperm,activation,PI3K,Akt,implicated,pathologic,changes,dysregulated,aortic,tissue,Our,data,demonstrate,reprogrammed,cells,from,germline,mature,gametes,contributes,development,This,broadens,current,knowledge,regarding,effect,cumulative,early,life,environmental,factors

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