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• W66193323 abstract "Placenta growth factor (PlGF), a member of the vascular endothelial growth factor(VEGF) protein family, is a critical regulator of vascular growth during processes oftissue remodelling including tissue repair and carcinogenesis. As reported for VEGF-A,the PlGF gene gives raise to different protein isoforms by mRNA splicing, which differprimarily in the presence or absence of a carboxyl-terminal domain, rich in basic aminoacids (so called heparin-binding domain). The most abundantly expressed isoforms arePlGF-1 (lacking the heparin-binding domain) and PlGF-2 (expressing the heparinbindingdomain). Whereas in recent years the heparin-binding domain of VEGF-A165, themajor VEGF-A isoform that shares 46% amino acid sequence identity with PlGF-2, hasemerged as essential domain for VEGF-A function, up to date little is known about thefunctional relevance of this domain present in PlGF-2. The aim of this project was toinvestigate the functional impact of the heparin-binding domain for PlGF-mediatedactivities.rhPlGF-1 and rhPlGF-2 were synthesized in HEK293 cells and used to performdifferential structural and functional in vitro and in vivo bioassays. Analysis of proteasesensitivity revealed that rhPlGF-2 is a target of the serine protease plasmin. Westernblotanalysis and MALDI-TOF-mass-spectrometry of plasmin-digested rhPlGF-2fragments identified a specific plasmin cleavage site (Lys118-Met119) resulting in loss ofthe C-terminal domain comprising the heparin-binding domain encoded by exon 6 and ashort stretch of eight amino acids encoded by exon 7. The biological relevance ofproteolytic cleavage of rhPlGF was corroborated by identifying a rhPlGF-2 cleavagefragment in non-healing, poorly vascularized human skin wounds, that was consistentwith plasmin mediated cleavage. To characterize the functional consequences ofplasmin-mediated cleavage of rhPlGF-2, a truncated form of rhPlGF (PlGFStop) wasgenerated, representing the plasmin-resistant N-terminal fragment (Leu1-Lys118).Chemotaxis and endothelial cell sprouting analysis revealed striking differences amongthe PlGF isoforms. Whereas rhPlGF-2 induced a robust chemotactic and endothelial cellsprouting response on HUVE and porcine endothelial cells stably transfected withNeuropilin-1 (PAE/Nrp-1), the activity of rhPlGF-1, plasmin processed rhPlGF-2 and therhPlGFStop mutant was significantly attenuated. Furthermore, the induction of avascularized granulation tissue in wounds of impaired healing diabetic mice could besignificantly stimulated by topical application of rhPlGF-2, whereas application ofrhPlGF-1 or rhPlGFStop showed weak effects. These findings indicate that the heparinbindingdomain of PlGF-2 stimulates endothelial cell functions in vitro and promotesangiogenesis in vivo. To unravel the underlying molecular mechanisms for the increasedbiological potency of PlGF-2, binding to diverse extracellular matrix components and theVEGFR-1 co-receptor Nrp-1 as well as signalling pathways were investigated.Surface Plasmon Resonance spectroscopy demonstrated a high affinity of rhPlGF-2, butunexpectedly also of rhPlGF-1 for several glycosaminoglycanes (heparin, heparansulphate and chondroitin sulphate). These findings indicate that the binding capacity ofPlGF to the selected glycosaminoglycanes is dependent on the amino acids encoded byexon 7, which is present in both isoforms. The heparin-binding domain presentexclusively in PlGF-2 appears not to be essential for binding of the investigated GAGs.rhPlGF-2 revealed a moderate binding to Nrp-1, which was significantly increased in thepresence of heparin. The absence of the entire C-terminal domain encoded by exon 6and 7 (represented by the rhPlGFStop mutant) resulted in complete loss of any testedbinding capacity. Activation of VEGFR-1 appears to be independent of the C-terminaldomain, because all isoforms rhPlGF-2 and rhPlGFStop resulted in an activation ofVEGFR-1 and its downstream targets Akt and Erk-1/-2. Analysis of signalling pathwaysin endothelial cells suggested that increased rhPlGF-2-induced cellular responses werein part mediated by increased activation of tyrosine kinases FAK (focal adhesion kinase)and Src family kinases. In addition, activation of both kinases was enhanced by Nrp-1overexpression and exposure of endothelial cells to collagen I.Collectively, our findings propose novel functions of the heparin-binding domain of PlGF-2 and of the C-terminal domain of PlGF-1 and indicate that plasmin-mediated proteolysisis a major switch to control PlGF-mediated angiogenesis." @default.
• W66193323 created "2016-06-24" @default.
• W66193323 creator A5014153780 @default.
• W66193323 date "2011-02-14" @default.
• W66193323 modified "2023-09-27" @default.
• W66193323 title "Functional characterization of the PlGF-2 heparin-binding domain" @default.
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