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• • • • • • • • • • • • • NAGNAGP5CSCPS-‐1NAGNAGNAG NAGNCGNCGNAG --• • 2ADP+PiCO2+NH3+H2O2ATPCPS-NAGNO NOS nNOS— iNOS— eNOS—m-‐TORTLR4 NF k BNO-‐HSP70 NO-‐VEGFPPARγFig. 1. Angiogenesis and vasculogenesis forming vessels: (A) angiogenesis: it occurs iniNally with the formaNon of the budding (1) or endothelial cell outgrowth followed by stretching (2) of small vessels and branching by proliferaNon (3) of exisNng endothelial cells and remodeling (4); (B) vasculogenesis: it is the growth of capillaries from pre-‐exisNng vessels (1 and 2), aYer formaNon of vascular (capillary) tubes, these undifferenNated vessels fuse forming a conNnuous vascular structure (3 and 4). • • • • • • • • • • • mmol/lWu1996• Wu2004• • Kim SW & Wu G (2004) J Nutr 134: 625-‐630 Yao K et al. (2008) 138: 867-‐872 NO mTOR • • • • • ((’&’&((&&&4&(&4&&4&1!#$%#&’()*+%*,-.%/0$%12%34’2%5#-6789:-6;-=?@ABC()A&DEFGHI#JK.LMNO.JKPQRJKSTUVPMWX%Y5#RZ[\]^_‘ab[\cb?defgh]i9:?_‘jk_:lemn()opqrqs!tu‘&’STvwxy‘5zp(){|/}izp~$%&’334-6/34/0ST3/05//0i:()/025*WuMeininger(20002002)Flynn(2002)!!#$%%&’()*+,-./0123456789:;=?@AB/CDE@!!((’&’&((&&&4&(&4&&4&1!#$%#&’()*+%*,-.%/0$%12%34’2%5#-6789:-6;-=?@ABC()A&DEFGHI#JK.LMNO.JKPQRJKSTUVPMWX%Y5#RZ[\]^_‘ab[\cb?defgh]i9:?_‘jk_:lemn()opqrqs!tu‘&’STvwxy‘5zp(){|/}izp~$%&’334-6/34/0ST3/05//0i:()/025*WuMeininger(20002002)Flynn(2002)!!#$%%&’()*+,-./0123456789:;=?@AB/CDE@!!• 12-‐5-‐• • • • • previouslyidentifiedbutmayresultfromdecreasesincellularactivitiesofbothP5CsynthaseandNAGsynthase.Thisintriguingfindingalsoraisedanimportantquestionofwhetherarginineisinsufficientforsupportingthemetabolicneedsof7-to21-d-oldsow-rearedpiglets(16,21).Argininedeficiencyinsow-rearedpigletsBecauseofthepracticallimitationinconductinganitro-gen-balancestudywithsow-rearedpiglets,wedecidedtomea-sureplasmabiochemicalvariables(e.g.,arginine,ammonia,andnitriteplusnitrate,stableoxidationproductsofNO)asindicatorsofargininestatusinpiglets(33).Therationalewasasfollows:1)arginineplaysacrucialroleinammoniadetox-ificationviathehepaticureacycleandisthephysiologicalsubstrateforNOsynthesis(30);2)adecreaseinplasmaarginineconcentrationsandanincreaseinplasmaammonialevelsaresensitiveindicatorsofargininedeficiencyinneo-nates,includingpiglets(2,9);and3)plasmaconcentrationsofnitriteplusnitratereflecttheavailabilityofarginineforsup-portingsystemicNOsynthesisinneonates(34).Ourresultsshowedthatplasmalevelsofmostaminoacidsdidnotchangeinpigletsduringthesucklingperiod(33),suggestingthatmechanismsexistformaintainingtheirho-meostasis.However,plasmaconcentrationsofarginineanditsimmediateprecursors(ornithineandcitrulline)decreasedpro-gressivelyby20–41%,withincreasingpostnatalagefrom3to14d(33).Intriguingly,asubstantialdecreaseinarginineavailabilityoccursaroundthetime(d8oflife)(33)whensow-rearedpigletsbegintoexhibitsubmaximalgrowth(13).Inaddition,plasmaconcentrationsofammoniaincreasedpro-gressivelyby18–46%,whereasthoseofnitriteplusnitratedecreasedby16–29%,in7-to14-d-oldsucklingpigs,com-paredwith1-to3-d-oldpigs.Thesemetabolicdataonim-pairedhepaticureagenesisandreducedsystemicNOsynthesissuggestahithertounrecognizeddeficiencyofargininein7-to21-d-oldsow-rearedpigs.Althoughpigletscontinuetogrowduringthe21-dsucklingperiod,thisdoesnotnecessarilymeanthatargininesupplyfrommilkplusendogenoussynthesismeetsargininerequirementsfortheirmaximalgrowth(ama-jorgoalofanimalproduction)andoptimalmetabolicfunc-tion,asexemplifiedbysubmaximalgrowthandimpairedNOsynthesisinarginine-deficientyoungrats(35).Argininedeficiencyasagrowth-limitingfactorinyoungpigsAsnotedabove,argininecontentisrelativelylowinsow’smilk(14,15),asreportedforthemilkofhumansandcows(14).Thereisexperimentalevidencesupportingthenotionthatareducedavailabilityofargininemaylimitthemaximalgrowthofyoungpigs.Forexample,Leibholz(36)reportedthatinpigletsweanedat3to4dofagesupplementing0.2and0.4%argininetoadriedmilkdietcontaining19.2%crudeproteinand0.75%arginine(sim