Abstract 5758: The Anti-Angiogenic Activity of rPAI-123 Promotes Vasa Vasorum Regression in Atherogenic Mice Through a Plasmin-Dependent Mechanism
Introduction: Angiogenic vasa vasorum is considered the conduit for nutrient supplies to atherosclerotic plaque and its inhibition is associated with reduced plaque progression. We reported that the anti-angiogenic activity of rPAI-123, a truncated PAI-1 protein, stimulates a highly significant decrease in vasa vasorum vessel area and length, plaque area and plaque cholesterol in the descending aorta in atherogenic mice. High levels of FGF-2 associated with adventitial vascular structures of saline treated mice appear to stimulate tube formation and vessel guidance, which is inhibited by rPAI-123.
Objective: In this study we investigated the mechanism of angiogenic vasa vasorum regression in atherogenic mice treated with rPAI-123.
Methods and results: Plasma from female LDLR−/−/ApoB-100 mice fed Paigen’s diet without cholate for 20 weeks while receiving rPAI-1 23 treatment (n = 21) for the last six weeks was compared to control mice treated with saline (n= 16). The rPAI-123 treated mice have significantly elevated plasmin, MMP-3 and MMP-2 activities accompanied by increased fibrinogen breakdown. Protease activities correspond with basement membrane breakdown visualized in confocal microscopy images of nidogen-probed adventitia. Immunoprecipitation of descending aorta adventitial protein pulls down a fibrinogen• FGF-2 complex in both treatment groups, but FGF-2 and fibrinogen levels are significantly less in rPAI-123 treated mice. In vitro studies show that FGF-2• fibrinogen complexes increase endothelial cell permeability and tube formation by 3- and 4-fold, respectively; rPAI-123 inhibits both angiogenic processes.
Conclusion: In conclusion, rPAI-123 promotes vasa vasorum regression in atherogenic female LDLR−/−/ApoB-100 mice through a plasmin-dependent mechanism that negatively regulates the fibrinogenic and angiogenic pathways. Enhanced plasmin activity, in response to rPAI-123, stimulates activation of MMPs known to degrade basement membrane and fibrinogen, thus leading to vessel collapse. Fibrinogen degradation inhibits the angiogenic potential of the fibrinogen•FGF-2 complex.