A truncated plasminogen activator inhibitor-1 protein blocks the availability of heparin-binding vascular endothelial growth factor A isoforms.
We have made deletions of the porcine plasminogen activator inhibitor-1 (PAI-1) gene to obtain recombinant truncated PAI-1 proteins to examine functions of the PAI-1 isoforms. We previously reported that one recombinant truncated protein, rPAI-1(23), induces the formation of angiostatin by cleaving plasmin. The rPAI-1(23) protein is also able to bind urokinase plasminogen activator and plasminogen and then reduce the amount of plasmin that is formed. We have now prepared three different truncated rPAI-1 proteins and demonstrate that PAI-1 conformations control the release of heparin-binding vascular endothelial growth factor (VEGF) isoforms. The rPAI-1(23) isoform can regulate the functional activity of heparan sulfate-binding VEGF-A isoforms by blocking the activation of VEGF from heparan sulfate. The rPAI-1(23) conformation induced extensive apoptosis in cultured endothelial cells and thus reduced the number of proliferating cells. The rPAI-1(23) isoform inhibited migration of VEGF-stimulated sprouting from chick aortic rings by 65%, thus displaying a role in anti-angiogenic mechanisms. This insight into anti-angiogenic functions related to PAI-1 conformational changes could provide potential intervention points in angiogenesis associated with atherosclerotic plaques and cancer.
Mulligan-Kehoe
Mary Jo
MJ
Department of Surgery, Vascular Surgery Section, Dartmouth Medical School, Dartmouth College, Hanover, New Hampshire 03756, USA. mary.j.mulligan-kehoe@dartmouth.edu
Kleinman
Hynda K
HK
Drinane
Mary
M
Wagner
Robert J
RJ
Wieland
Courtney
C
Powell
Richard J
RJ
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002417:Cattle; D002478:Cells, Cultured; D002642:Chick Embryo; D003470:Culture Media; D017931:DNA Primers; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006493:Heparin / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008222:Lymphokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010958:Plasminogen / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000737:chemistry / Q000502:physiology*; D011485:Protein Binding; D013552:Swine; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D003470:Culture Media; D017931:DNA Primers; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D017395:Plasminogen Activator Inhibitor 1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D010958:Plasminogen; D006493:Heparin; D014568:Urokinase-Type Plasminogen Activator