Angiogenesis, proteases and angiogenic factors during the inception of pregnancy. Crucial contributors or trivial bystanders?
Hele tekst
(2) $PMPVS'JHVSFT.
(3)
(4) $PMPVS¹HVSFT. $)"15&3 Sprouting. Intussusception. Elongation. 'JHVSF&OEPNFUSJBMBOHJPHFOFTJTQSPDFFETCZFMPOHBUJPOBOEJOUVTTVTDFQUJPOSBUIFSUIBOCZDMBTTJDBM TQSPVUGPSNBUJPO"EBQUFEGSPN3PHFST. .
(5) $)"15&3. B. C. D 100 75. . 50 #. 25 0. Control uPA BB94 uPA +BB94. mean tube length (% of control). . mean tube length (% of control). $PMPVS¹HVSFT. A. E 100 75 50 25 0. Control uPA BB94 uPA +BB94. 'JHVSF$BQJMMBSZMJLFUVCFGPSNBUJPOCZI&.7&$JOB¹CSJOPSDPMMBHFONBUSJYEFQFOETPOV1"BOE..1 BDUJWJUJFT I&.7&$XFSFDVMUVSFEPOUPQPGBUISFFEJNFOTJPOBM¹CSJONBUSJY " $ % PS¹CSJODPMMBHFOUZQF NBUSJY # & BOETUJNVMBUFEXJUI7&('" OHN- "BOE#.JDSPHSBQITUBLFOBGUFSEBZTPGDVMUVSJOH JOTFUTJO"BOE#TIPXEFUBJMTPGDBQJMMBSZMJLFTUSVDUVSFT#BSμN #BSJOTFUTμN$$SPTT TFDUJPOQFSQFOEJDVMBSUPUIFNBUSJYTVSGBDFBOETUBJOFEXJUI)FNBUPYZMJO1IMPYJOF4BGSBO CBSμN %BOE&I&.7&$XFSFDVMUVSFEXJUIOHN-7&('" DPOUSPM JOUIFBCTFODFPSQSFTFODFPGQPMZDMPOBM BOUJV1" αV1" μHN- ## μHN- PS B DPNCJOBUJPO PG ## BOE BOUJV1" "GUFS EBZT PGDVMUVSJOH NFBOUVCFMFOHUIXBTNFBTVSFECZJNBHFBOBMZTJT5IFEBUBJOQBOFM%BSFFYQSFTTFEBTB QFSDFOUBHF PG 7&('"JOEVDFE UVCF GPSNBUJPO ± 4&. PG JOEFQFOEFOU FYQFSJNFOUT PG EVQMJDBUF XFMMT QFSGPSNFEXJUIEJGGFSFOUI&.7&$JTPMBUJPOT1BOFM&SFQSFTFOUTFYQFSJNFOUT∗1WTDPOUSPM 1WTαV1".
(6) $PMPVS¹HVSFT. kD. A. 92. -MMP-9. active MT1-MMP 8 (ng/mL). B. 7. 72 64. kD. 3. -pro-MMP-2 -act. MMP-2. 642. 55. -MMP-1/3. M. Con TNF PMA VEGF. D. C. 1 0. MT3MMP. 46-. Con VEGF TNF V/T Con. VEGF TNF PMA. E. 'JHVSFI&.7&$FYQSFTTWBSJPVT..1TBOE.5..1T I&.7&$XFSFDVMUVSFEGPSIJO.TVQQMFNFOUFEXJUI)4" " PS)4 # $ BOEXFSF OPU TUJNVMBUFE DPOUSPM PS TUJNVMBUFE XJUI 5/'α OHN- 7&('" OHN- PS 1." . BTJOEJDBUFE"(FMBUJO[ZNPHSBQIZPGIDPOEJUJPOFENFEJVN .MBEEFS #.5..1BDUJWJUZJO DFMMMZTBUFT NFBOSBOHFPGUXPFYQFSJNFOUTQFSGPSNFEJOEVQMJDBUFXFMMTXJUIUXPEJGGFSFOUJTPMBUJPOT EFUFDUJPOMJNJUPGUIFBTTBZOHN- $8FTUFSOCMPUPG.5..1JOIDPOEJUJPOFENFEJVN%BOE &*NNVOPIJTUPDIFNJDBMBOBMZTJTPG.5..1JOFOEPNFUSJBMUJTTVFTIPXTUIFQSFTFODFPG.5..1JO FOEPUIFMJBMDFMMT % BSSPXT BOENZPNFUSJVN & TUBST . .
(7) $)"15&3. A Total Vascular Surface (mm 2/mm 2). 0,06. . 0,05 0,04 0,03 0,02 0,01 0 EP. #. #. #. 200. Luminal surface (um /vessel). 250. LS. M. ES. LS. M. 600 500. $. 2. 2. Number of vessels / mm. $PMPVS¹HVSFT. ES. D. C. . LP. 150 100 50 0 EP. LP. ES. LS. M. 400 300 200 100 0 EP. LP. 'JHVSF7BTDVMBSJTBUJPOQBUUFSOJODZDMJOHIVNBOFOEPNFUSJVN 5IF WBTDVMBSJTBUJPO QBUUFSO JO IVNBO FOEPNFUSJVN XBT EFUFSNJOFE CZ JNBHF BOBMZTJT PG BOUJ$% TUBJOFETFDUJPOT4JY¹FMETQFSCJPQTZXFSFTDBOOFEBUYNBHOJ¹DBUJPO"$%BOUJHFOFYQSFTTJPOJO FOEPUIFMJBMDFMMTJOMBUFQSPMJGFSBUJWFFOEPNFUSJVN CBSμN #5IFUPUBMWBTDVMBSTVSGBDF NNNN $UIFOVNCFSPGWFTTFMTQFSNNBOE%UIFMVNJOBMTVSGBDF μNWFTTFM XFSFDBMDVMBUFEGPSFBDITBNQMF BOEFYQSFTTFEBTNFBO4&.&1&BSMZQSPMJGFSBUJWFQIBTF O -1-BUFQSPMJGFSBUJWFQIBTF O &4 &BSMZTFDSFUPSZQIBTF O -4-BUFTFDSFUPSZQIBTF O .NFOTUSVBMQIBTF O •QWFSTVT &1 &4BOE-4#QWFSTVT&1 &4∗QWFSTVT&4 -4BOE.BOEQWFSTVT&4 -4BOE..
(8) $PMPVS¹HVSFT. A. MT1-MMP. B. MT1-MMP + actin. G. MT4-MMP. C. MT2-MMP. D. MT2-MMP + actin. H. v WF. E. MT3-MMP. F. MT3-MMP + actin. I. Lysotracker. 'JHVSF.5..1BOUJHFOFYQSFTTJPOTJOI&.7&$ &OEPUIFMJBM .5..1 FYQSFTTJPO XBT EFUFSNJOFE CZ ºVPSFTDFODF NJDSPTDPQZ NBHOJ¹DBUJPO Y 5IF FYQSFTTJPOPG.5..1 BDUJO" # .5..1 BDUJO$ % .5..1 BDUJO& ' .5..1 ( WPO8JMMFCSBOE'BDUPSJO8FJCFM1BMBEFCPEJFT ) BOE-ZTPUSBDLFSJOMZTPTPNFT * JODVMUVSFEFOEPNFUSJBM FOEPUIFMJBMDFMMT I&.7&$ 5IFOFHBUJWFDPOUSPMPOMZTIPXFECMVFTUBJOJOHPGUIFOVDMFJ OPUTIPXO #MVF %"1*JOOVDMFJ HSFFOUBSHFUQSPUFJO SFEBDUJOPSMZTPUSBDLFS. .
(9) Mean Staining Index. A. 4. 3. 2. 1. 0 MT2-MMP. MT3-MMP. C. MT2-MMP. D. MT3-MMP. E. MT4-MMP. $PMPVS¹HVSFT. B. MT1-MMP. MT4-MMP. . 'JHVSF.5..1BOUJHFOFYQSFTTJPOTJOFOEPNFUSJBMFOEPUIFMJVNBOEPUIFSDFMMUZQFT 5IF FYQSFTTJPO PG .5..1 BOUJHFOT CZ FOEPNFUSJBM FOEPUIFMJBM DFMMT XBT EFUFSNJOFE CZ JNNVOPIJTUPDIFNJTUSZ".5..1BOUJHFOFYQSFTTJPOTJOFOEPUIFMJBMDFMMTFYQSFTTFEQFSDZDMFQIBTFBT NFBOTUBJOJOHJOEFY4&. BMMQ 5IFTUBJOJOHJOEFYJTNJOJNBMMZ OPTUBJOFEDFMMT BOENBYJNBMMZ TUSPOHMZTUBJOFEDFMMT #.5..1BOUJHFOEFUFDUFEJO14.$T PQFOBSSPX CVUOPUJOFOEPUIFMJBM DFMMT BSSPXT JOMBUFQSPMJGFSBUJWF -1 FOEPNFUSJVN$.5..1BOUJHFOFYQSFTTJPOJOFOEPUIFMJVNJO-1 FOEPNFUSJVN BSSPX %.5..1FYQSFTTJPOJOFOEPUIFMJBMDFMMT BSSPXT BOETUSPNBMDFMMT PQFOBSSPX JO-1FOEPNFUSJVN&.5..1FYQSFTTJPOJOFOEPUIFMJBMDFMMT BSSPX JO-1FOEPNFUSJVN'/FHBUJWF DPOUSPM#BSμN &BSMZQSPMJGFSBUJWFQIBTF O -BUFQSPMJGFSBUJWFQIBTF O &BSMZTFDSFUPSZQIBTF O. -BUFTFDSFUPSZQIBTF O NFOTUSVBMQIBTF O .
(10) $PMPVS¹HVSFT. $)"15&3 DB. DSE. DP. DB. Õ. DP. Õ. DSE. Õ. Cytokeratin. A. B. C. 0,08. 5000. *. . *. . 2. 0,06. 2. 125. Vascular Surface (mm /mm ). 2. Number of vessels / mm. 150. Luminal Surface (um 2/vessel). CD34. 100. 75 50. 25 0. 0,04. 0,02. DP. DB. . 3000. 2000. 1000. 0. 0. DSE. * 4000. DSE. DP. DB. DSE. DP. DB. 'JHVSF$ZUPLFSBUJOFYQSFTTJPOBOEWBTDVMBSJTBUJPOJOUIFUISFFEFDJEVBMUJTTVFT %JGGFSFOUJBUJPO CFUXFFO UISFF EFDJEVBM UJTTVFT XBT PCUBJOFE CZ )14 BOE BOUJDZUPLFSBUJO TUBJOJOH UPQ QBOFM %4& BOE %1 FYQSFTTFE DZUPLFSBUJO POMZ JO HMBOEVMBS FQJUIFMJBM DFMMT DMPTFE BSSPXT XIFSFBT DZUPLFSBUJOJTBMTPFYQSFTTFEJOFYUSBWJMMPVTUSPQIPCMBTUTPG%# PQFOBSSPXT 5IFWBTDVMBSJTBUJPOQBUUFSO JOIVNBOEFDJEVBMUJTTVFTXBTEFUFSNJOFECZJNBHFBOBMZTJTPGBOUJ$%TUBJOFETFDUJPOT NJEEMFBOE CPUUPNQBOFM $%BOUJHFOFYQSFTTJPOJOFOEPUIFMJBMDFMMT BSSPXT PG%4& %1BOE%#XBTDPNQBSFE XJUIJOTVCKFDUT%BUBXFSFBOBMZTFEVTJOHUIFSFQFBUFENFBTVSFT"/07""5IFOVNCFSPGWFTTFMTQFS NN #UIFWBTDVMBSTVSGBDFQFSBSFB NNNN BOE$UIFMVNJOBMTVSGBDF μNWFTTFM XFSFDBMDVMBUFE BOEFYQSFTTFEBTNFBO4&.∗Q♦Q#BSμN. .
(11) $PMPVS¹HVSFT . 'JHVSF1SPUFJOFYQSFTTJPOPGBOHJPHFOJDGBDUPSTJOFOEPUIFMJVNPGFBSMZ¹STUUSJNFTUFSEFDJEVB 5IFQSPUFJOFYQSFTTJPOPGBOHJPHFOJDGBDUPSTXBTEFUFSNJOFEJO%4& %1BOE%#'SJFENBOUFTU BOPO QBSBNFUSJDBMUFTUGPSQBJSFETBNQMFT BOEUIF8JMDPYPOUFTUXFSFVTFEGPSTUBUJTUJDBMBOBMZTJT"1SPUFJO FYQSFTTJPOPGFBDIBOHJPHFOJDGBDUPSJOFOEPUIFMJVNXBTFYQSFTTFEBTUIFNFBOTUBJOJOHJOEFY4&.BOE #)TIPXFYBNQMFTPGUIFTFFYQSFTTJPOT#&OEPUIFMJBM7&('FYQSFTTJPOXBTOPUEFUFDUBCMFJO%#$1M(' XBT FYQSFTTFE JO FQJUIFMJVN PQFO BSSPX BOE FOEPUIFMJVN DMPTFE BSSPX PG %# % &OEPUIFMJBM ,%3 FYQSFTTJPO DMPTFEBSSPX BOETUSPNBM,%3FYQSFTTJPO PQFOBSSPX JO%#&&OEPUIFMJBM'MUFYQSFTTJPO JO%# BSSPX '"OHJPQPJUFJOJO%#XBTEFUFDUFEJOFQJUIFMJVN PQFOBSSPX CVUOPUJOTUSPNBMBOE FOEPUIFMJBM DFMMT DMPTFE BSSPX ( &OEPUIFMJBM BOHJPQPJFUJO FYQSFTTJPO JO %# BSSPX ) &OEPUIFMJBM 5*&FYQSFTTJPOJO%# BSSPX %4& %1 %##BSμN FYDFQU'μN .
(12) $PMPVS¹HVSFT. 'JHVSF1SPUFJOFYQSFTTJPOPGBOHJPHFOJDGBDUPSTJOFYUSBWJMMPVTUSPQIPCMBTUT &75 PGFBSMZ¹STUUSJNFTUFS EFDJEVB 5IFQSPUFJOFYQSFTTJPOPGBOHJPHFOJDGBDUPSTJO&75JOEFDJEVBCBTBMJT %# XBTTUVEJFEJOTFSJBMTFDUJPOT TUBJOFEBHBJOTUDZUPLFSBUJOBOEUIFUBSHFUQSPUFJO"1SPUFJOFYQSFTTJPOJO&75XBTFYQSFTTFEBTUIFNFBO TUBJOJOHJOEFY4&.#$ZUPLFSBUJO BSSPXT BOE$TFSJBM1M('FYQSFTTJPO BSSPXT JO&75#BSμN. 'JHVSF 7BTDVMBSJTBUJPO QBUUFSO BOE FOEPUIFMJBM QSPUFJO FYQSFTTJPO JO FBSMZ WFSTVT MBUF ¹STU USJNFTUFS EFDJEVB 5IFWBTDVMBSJTBUJPOQBUUFSOJOIVNBOFBSMZ CMBDLCBST BOEMBUF XIJUFCBST ¹STUUSJNFTUFSEFDJEVBMUJTTVFT XBTEFUFSNJOFECZJNBHFBOBMZTJTPGBOUJ$%TUBJOFETFDUJPOT%BUBXFSFBOBMZTFEVTJOHUIFSFQFBUFE NFBTVSFT"/07""5IFOVNCFSPGWFTTFMTQFSNN #UIFWBTDVMBSTVSGBDFQFSBSFB NNNN BOE$ UIFMVNJOBMTVSGBDF μNWFTTFM XFSFFYQSFTTFEBTNFBO4&.7&('FYQSFTTJPOXBTOPUEFUFDUBCMFJO FBSMZ¹STUUSJNFTUFSFOEPUIFMJVNPG%# BSSPX % XIFSFBTUIFFYQSFTTJPOXBTQSFTFOUJOMBUF¹STUUSJN FOEPUIFMJVNPG%# BSSPX & &BSMZ¹STUUSJNFTUFSBOEMBUF¹STUUSJNFTUFS#BSμN ∗Q. .
(13) B. C. Õ. Õ. A. Õ. $)"15&3. Õ E. $PMPVS¹HVSFT. Õ. Õ . F. Õ. D. 'JHVSF1SPUFJOMFWFMTPGQSPUFBTFTJOFBSMZ¹STUUSJNFTUFSEFDJEVB 5IFMFWFMPGQSPUFBTFTXBTEFUFSNJOFEJO%4& %1BOE%#".5..1BOUJHFOXBTEFUFDUBCMFJOFQJUIFMJBM PQFO BSSPX FOEPUIFMJVN DMPTFE BSSPX BOE TUSPNBM DFMMT DMPTFE BSSPXIFBE PG %4& # .5..1 BOUJHFOJOFQJUIFMJVN PQFOBSSPX TUSPNBMDFMMT DMPTFEBSSPXIFBE BOEQFSJDZUFT PQFOBSSPXIFBE PG %# $ &QJUIFMJBM PQFO BSSPX BOE TUSPNBM DMPTFE BSSPXIFBE .5..1 BOUJHFO JO %# 1FSJDZUFT OPU QSFTFOU JO UIJT ¹FME % .5..1 BOUJHFO JO FQJUIFMJVN PQFO BSSPX BOE POMZ EJNMZ JO TUSPNBM DFMMT DMPTFEBSSPXIFBET PG%1&V1"BOUJHFOJOFQJUIFMJVN PQFOBSSPX TUSPNBMDFMMT DMPTFEBSSPXIFBE BOE FOEPUIFMJVN DMPTFE BSSPXT JO %# 1FSJDZUFT OPU QSFTFOU JO UIJT ¹FME ' &QJUIFMJBM PQFO BSSPX FOEPUIFMJBM DMPTFEBSSPXT BOETUSPNBMDFMMT DMPTFEBSSPXIFBET V1"3QSPUFJOJO%#"% '#BS μN &#BSμN.
(14) $PMPVS¹HVSFT. A. 1,8 M ea n Sta ining Index. 1,6. DSE. 1,4. DP. 1,2. DB. 1 0,8 0,6 0,4 0,2 0 MT 1-MMP MT 2-MMP MT 3-MMP MT 5-MMP. B. C. E. uPA. uPAR. D. F. Õ 'JHVSF1SPUFJOMFWFMTPGQSPUFBTFTJOFOEPUIFMJVNPGFBSMZ¹STUUSJNFTUFSEFDJEVB "1SFTFODFPGQSPUFBTFBOUJHFOTJOFOEPUIFMJVN &$ XBTFYQSFTTFEBTUIFNFBOTUBJOJOHJOEFY4&.BOE #'TIPXFYBNQMFTPGFOEPUIFMJBMQSPUFBTFFYQSFTTJPO#&OEPUIFMJBM BSSPXT BOETUSPNBM BSSPXIFBET .5..1XBTEFUFDUBCMFJO%#$.5..1XBTEFUFDUFEJOFOEPUIFMJVN BSSPXT PG%#%&OEPUIFMJBM .5..1 BOUJHFO BSSPXT JO %4& & V1" BOUJHFO JO FOEPUIFMJVN DMPTFE BSSPXT FQJUIFMJVN PQFO BSSPX BOETUSPNBMDFMMT BSSPXIFBE JO%#'V1"3JO%#XBTEFUFDUFEJOFOEPUIFMJBMDFMMT BSSPXT BOE TUSPNBMDFMMT BSSPXIFBET #'#BSμN. .
(15) A. SynCTB. 7. CTB. Mean Staining Index. 6 5 4 3 2 1 0 MT 1MMP. MT 3MMP. MT 5MMP. uPA. uPAR. D. uPA. C. Cytokeratin. Õ. Õ. B. uPAR. MT 2MMP. A. CD56. *. Early 1st trimester 20. *. * *. Late 1st trimester. 15 10 5 0 DSE. DP. 4 M ea n % po sitiv e cells/stro m a l cells. 25 M ea n % po sitiv e cells/stro m a l cells. $PMPVS¹HVSFT. Õ. . 'JHVSF1SPUFJOMFWFMTPGQSPUFBTFTJOWJMMPVTBOEFYUSBWJMMPVTUSPQIPCMBTUT &75 PGFBSMZ¹STUUSJNFTUFS EFDJEVB 5IF QSFTFODF PG QSPUFBTF BOUJHFOT JO WJMMPVT BOE FYUSBWJMMPVT USPQIPCMBTUT JO EFDJEVB CBTBMJT %# XBT TUVEJFEJOTFSJBMTFDUJPOTTUBJOFEBHBJOTUDZUPLFSBUJOBOEUIFUBSHFUQSPUFJO"*NNVOPTUBJOJOHJOTZODZUJP BOEDZUPUSPQIPCMBTUT TZO$5#BOE$5# XBTFYQSFTTFEBTUIFNFBOTUBJOJOHJOEFY4&.#BOE$V1"3 BOEDZUPLFSBUJOBOUJHFOTJOTFSJBMFYQSFTTJPOJO&75 DMPTFEBSSPXT BOEFQJUIFMJVN PQFOBSSPXT %V1" BOUJHFOT JO TZODZUJPUSPQIPCMBTU PQFO BSSPX BOE OPU JO DZUPUSPQIPCMBTU DMPTFE BSSPX #% #BS μN. DB. 3,5 3. B. CD68 Early 1st trimester Late 1st trimester. 2,5 2 1,5 1 0,5 0 DSE. DP. DB. D. CD68. C. CD56. E. Negative. 'JHVSF$%BOE$%QPTJUJWFDFMMTJOFBSMZBOEMBUF¹STUUSJNFTUFSEFDJEVB " $%QPTJUJWF DFMMT JO EFDJEVB FYQSFTTFE BT UIF NFBO OVNCFS PG QPTJUJWF DFMMT QFS UPUBM OVNCFS PG TUSPNBMDFMMT NFBO4% #$%QPTJUJWFDFMMTJOEFDJEVB FYQSFTTFEBTUIFNFBOOVNCFSPGQPTJUJWF DFMMTQFSUPUBMOVNCFSPGTUSPNBMDFMMT NFBO4% $$%FYQSFTTJPOJOEFDJEVBCBTBMJT CBSμN #MPXVQTIPXT$%
(16) DFMMT BSSPXT TVSSPVOEJOHBWFTTFMBOEHMBOE CBSμN%$%QPTJUJWFDFMM BSSPX JOEFDJEVBQBSJFUBMJT CBSμN&/FHBUJWFDPOUSPM CBSμN QWFSTVT%4&.
(17) $PMPVS¹HVSFT. DSE. Õ Õ Decidual Secretory Endometrium (DSE) DSE versus DB Extravillous Trophoblast Pregnancy-induced Hormones * Uterine NK cells. DSE versus DP Pregnancy-induced Hormones * Uterine NK cells. Decidua Parietalis (DP). DP. Decidua Basalis (DB). DP versus DB Extravillous Trophoblast. DB. Õ Õ 'JHVSF)VNBO¹STUUSJNFTUFSEFDJEVBMUJTTVFT 3FQSFTFOUBUJPO PG UIF JOºVFODFT PG JNNVOF DFMMT FYUSBWJMMPVT USPQIPCMBTU BOE QSFHOBODZJOEVDFE IPSNPOFT I$( PFTUSBEJPMBOEQSPHFTUFSPOF PO¹STUUSJNFTUFSEFDJEVBMUJTTVFT%JGGFSFOUJBUJPOCFUXFFO EFDJEVBMTFDSFUPSZFOEPNFUSJVN %4& EFDJEVBQBSJFUBMJT %1 BOECBTBMJT %# XBTPCUBJOFECZ)14 BOEDZUPLFSBUJOTUBJOJOH%4&BOE%1FYQSFTTDZUPLFSBUJOJOHMBOEVMBSFQJUIFMJVN PQFOBSSPXT XIFSFBT DZUPLFSBUJOJTBMTPFYQSFTTFEJO&75 DMPTFEBSSPXT PG%##BSμN. .
(18) $)"15&3 2. #. N u m b er o f vessels p er m m. 140 120 100 80. . 60 40 20 0. $PMPVS¹HVSFT. DSE. . . DP. DB. B. #. C. #. 0,08 0,07 0,06 0,05 0,04 0,03 0,02 0,01 0 DSE. DP. DB. L u m in al S u rface (u m 2 /vessel). 2. #. T o tal Vascu lar Su rface p er m m. A 160. #. #. 7000. . 6000. . 5000 4000 3000 2000 1000 0 DSE. Cases Decidua basalis. Cases Decidua parietalis. Controls Decidua basalis. Controls Decidua parietalis. DP. DB. 'JHVSF7BTDVMBSJTBUJPOQBUUFSOJODBTFTBOEDPOUSPMT 5IFWBTDVMBSJTBUJPOQBUUFSOJOEFDJEVBMUJTTVFTPGDPOUSPMT O CMBDLCBST BOEDBTFT O XIJUFCBST XBTEFUFSNJOFECZJNBHFBOBMZTJTPGBOUJ$%TUBJOFETFDUJPOT"7FTTFMEFOTJUZ OVNCFSPGWFTTFMTQFS NN #UIFUPUBMWBTDVMBSTVSGBDF NNNN BOE$UIFMVNJOBMTVSGBDF μNWFTTFM XFSFDBMDVMBUFE BOE FYQSFTTFE BT NFBO4&. Q XJUIJO DPOUSPMT ∗ Q JO DBTFT WFSTVT DPOUSPMT 5IF CPUUPN QBOFMTTIPXFYBNQMFTPGWBTDVMBSJTBUJPOJOEFDJEVBQBSJFUBMJTBOECBTBMJTPGDBTFTBOEDPOUSPMT.
(19) $PMPVS¹HVSFT. Controls. Cases. Ang-1. Flt-1. MT5-MMP. Negative. 'JHVSF"OUJHFOQSFTFODFPGBOHJPHFOJDGBDUPSTBOEQSPUFBTFTJODBTFTBOEDPOUSPMT &YBNQMFTPGUIFBOUJHFOFYQSFTTJPOPG"OH 'MUBOE.5..1JODPOUSPMT MFGUTJUFPGQBOFM BOEDBTFT SJHIUTJUFPGQBOFM "OHBOUJHFOQSFTFODFJOFQJUIFMJBMDFMMT PQFOBSSPX JO%#PGDPOUSPMT DPNQBSFEUP UIFJSQSFTFODFJOTUSPNBM DMPTFEBSSPX FQJUIFMJBMDFMMT PQFOBSSPX BOE14.$ PQFOBSSPXIFBE JO%# PGDBTFT'MUBOUJHFOQSFTFODFJOFQJUIFMJBMDFMMT PQFOBSSPX BOETUSPNBMDFMMT DMPTFEBSSPX JO%#PG DPOUSPMT DPNQBSFEUPUIFJSFMFWBUFEQSFTFODFJO%#PGDBTFT/PWBTDVMBUVSFQSFTFOUJOUIFTF¹MFET. ..1BOUJHFOTJOFQJUIFMJBMDFMMT PQFOBSSPX JO%#PGDPOUSPMT DPNQBSFEUPUIFJSQSFTFODFJO14.$ PQFO BSSPXIFBE FOEPUIFMJBM DMPTFEBSSPXIFBE TUSPNBM DMPTFEBSSPX JO%#PGDBTFT/FHBUJWFDPOUSPMTVTJOH OPOJNNVOFNPVTF*H( MFGU BOEPNJTTJPOPGUIF¹STUBOUJCPEZ SJHIU "MMQBOFMTCBSμN. .
(20) Controls. Cases. Flt-1. $PMPVS¹HVSFT. KDR. MT2-MMP. . 'JHVSF"OUJHFOQSFTFODFPGBOHJPHFOJDGBDUPSTBOEQSPUFBTFTJOFOEPUIFMJVNJODBTFTBOEDPOUSPMT 5IFQSPUFJOFYQSFTTJPOPGBOHJPHFOJDGBDUPSTBOEQSPUFBTFTXBTEFUFSNJOFEJO%4& %1BOE%#PGDBTFT BOEDPOUSPMTWJBJNNVOPIJTUPDIFNJTUSZ&YBNQMFTPGUIFEJGGFSFOUJBMFOEPUIFMJBMFYQSFTTJPO BSSPXIFBET PGºU ,%3BOE.5..1CFUXFFODBTFT SJHIUTJUFPGQBOFM BOEDPOUSPMT MFGUTJUFPGQBOFM BSFHJWFO 'MU &MFWBUFE ºU FYQSFTTJPO JO FOEPUIFMJBM DFMMT JO %# PG DBTFT DPNQBSFE UP DPOUSPMT ,%3 &MFWBUFE ,%3FYQSFTTJPOJOFOEPUIFMJBMDFMMTJO%#PGDBTFTDPNQBSFEUPDPOUSPMT.5..1&MFWBUFE.5..1 FYQSFTTJPOJOFOEPUIFMJBMDFMMTJO%#PGDBTFTDPNQBSFEUPDPOUSPMT"MMQBOFMTCBSμN.
(21)
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License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden. Downloaded
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