Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
Eunice Wairimu Maina
Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland
Hannu Koistinen
Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland; Helsinki University Hospital, Helsinki, Finland
Ulf-Håkan Stenman
Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland; Helsinki University Hospital, Helsinki, Finland
Kari Alitalo
Wihuri Research Institute, Helsinki, Finland; Helsinki University Hospital, Helsinki, Finland; Translational Cancer Medicine Research Program, University of Helsinki, Helsinki, Finland
Vascular endothelial growth factor-C (VEGF-C) acts primarily on endothelial cells, but also on non-vascular targets, for example in the CNS and immune system. Here we describe a novel, unique VEGF-C form in the human reproductive system produced via cleavage by kallikrein-related peptidase 3 (KLK3), aka prostate-specific antigen (PSA). KLK3 activated VEGF-C specifically and efficiently through cleavage at a novel N-terminal site. We detected VEGF-C in seminal plasma, and sperm liquefaction occurred concurrently with VEGF-C activation, which was enhanced by collagen and calcium binding EGF domains 1 (CCBE1). After plasmin and ADAMTS3, KLK3 is the third protease shown to activate VEGF-C. Since differently activated VEGF-Cs are characterized by successively shorter N-terminal helices, we created an even shorter hypothetical form, which showed preferential binding to VEGFR-3. Using mass spectrometric analysis of the isolated VEGF-C-cleaving activity from human saliva, we identified cathepsin D as a protease that can activate VEGF-C as well as VEGF-D.
