00539nas a2200145   4500008004100000245014500041210006900186260001600255300000800271490000700279100002100286700002100307700002100328856004400349       2021                        eng d00aProteolytic Cleavages in the VEGF Family: Generating Diversity among Angiogenic VEGFs, Essential for the Activation of Lymphangiogenic VEGFs0 aProteolytic Cleavages in the VEGF Family Generating Diversity am  cJan-02-2021  a1670 v101 aKünnapuu, Jaana1 aBokharaie, Honey1 aJeltsch, Michael  uhttps://www.mdpi.com/2079-7737/10/2/16702718nas a2200205   4500008004100000245007100041210006600112260001600178300001200194490000700206520212700213653002202340653001602362653001602378653001102394100002002405700002302425700002102448856004302469       2019                        eng d00aThe Proteolytic Activation of Vascular Endothelial Growth Factor-C0 aProteolytic Activation of Vascular Endothelial Growth FactorC  c2019/12/18/  a88 - 980 v233 aThe enzymatic cleavage of the protein backbone (proteolysis) is integral to many biological processes, e.g. for the break­down of proteins in the digestive system. Specific proteolytic cleavages are also used to turn on or off the activity of proteins. For example, the lymphangiogenic vascular endothelial growth factor-­C (VEGF-­C) is synthesized as a precursor molecule that must be converted to a mature form by the enzymatic removal of C-­ and N-­terminal propeptides before it can bind and activate its receptors. The constitutive C-­terminal cleavage is mediated by proprotein convertases such as furin. The subsequent ac­tivating cleavage can be mediated by at least four different proteases: by plasmin, ADAMTS3, prostate­-specific antigen (PSA) and cathepsin D. Processing by different proteases results in distinct forms of "ma­ture" VEGF­-C, that differ in their affinity and their receptor activation potential. This processing is tightly regulated by the CCBE1 protein. CCBE1 regulates the acti­vating cleavage of VEGF­C by ADAMTS3 and PSA, but not by plasmin. During embryonic development of the lymphatic system, VEGF-­C is activated primarily by the ADAMTS3 protease. In contrast, it is believed that plasmin is responsible for wound healing lymphangiogenesis and PSA for tumor-­associated pathological lym­phangiogenesis. Cathepsin D has also been implicated in tumor lymphangiogenesis. In addition, cathepsin D in saliva might activate latent VEGF­C upon wound licking, thereby accelerating wound healing. The molecular details of proteolytic activation of VEGF­-C are only recently extensively explored, and we likely do not know yet all activating proteases. It appears that the activity of VEGF­-C is regulated for different specific functions by different proteinases. Although VEGF­-C clearly plays a pivotal role for tumor progression and metastasis in experimental animal studies, the rele­vance of most correlative studies on the role of VEGF­-C in human cancers is quite limited until now, also due to the lack of methods to differentiate between inactive and active forms.10aLymphangiogenesis10aproteinases10aproteolysis10aVEGF-C1 aLackner, Marcel1 aSchmotz, Constanze1 aJeltsch, Michael  uhttps://doi.org/10.5281/zenodo.362926302389nas a2200289   4500008004100000245009100041210006900132260001400201300001300215490000800228520151500236100001701751700002001768700001501788700002301803700001901826700002301845700002101868700002401889700002401913700002301937700002601960700002201986700001802008700002402026856004902050       2005                        eng d00aPathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation0 aPathogenesis of persistent lymphatic vessel hyperplasia in chron  c2005/Feb/  a247 - 570 v1153 aEdema occurs in asthma and other inflammatory diseases when the rate of plasma leakage from blood vessels exceeds the drainage through lymphatic vessels and other routes. It is unclear to what extent lymphatic vessels grow to compensate for increased leakage during inflammation and what drives the lymphangiogenesis that does occur. We addressed these issues in mouse models of (a) chronic respiratory tract infection with Mycoplasma pulmonis and (b) adenoviral transduction of airway epithelium with VEGF family growth factors. Blood vessel remodeling and lymphangiogenesis were both robust in infected airways. Inhibition of VEGFR-3 signaling completely prevented the growth of lymphatic vessels but not blood vessels. Lack of lymphatic growth exaggerated mucosal edema and reduced the hypertrophy of draining lymph nodes. Airway dendritic cells, macrophages, neutrophils, and epithelial cells expressed the VEGFR-3 ligands VEGF-C or VEGF-D. Adenoviral delivery of either VEGF-C or VEGF-D evoked lymphangiogenesis without angiogenesis, whereas adenoviral VEGF had the opposite effect. After antibiotic treatment of the infection, inflammation and remodeling of blood vessels quickly subsided, but lymphatic vessels persisted. Together, these findings suggest that when lymphangiogenesis is impaired, airway inflammation may lead to bronchial lymphedema and exaggerated airflow obstruction. Correction of defective lymphangiogenesis may benefit the treatment of asthma and other inflammatory airway diseases.1 aBaluk, Peter1 aTammela, Tuomas1 aAtor, Erin1 aLyubynska, Natalya1 aAchen, Marc, G1 aHicklin, Daniel, J1 aJeltsch, Michael1 aPetrova, Tatiana, V1 aPytowski, Bronislaw1 aStacker, Steven, A1 aYlä-Herttuala, Seppo1 aJackson, David, G1 aAlitalo, Kari1 aMcDonald, Donald, M  uhttp://view.ncbi.nlm.nih.gov/pubmed/15668734