Plasminogen Activator Inhibitor-1 Protects Endothelial Cells from FasL-Mediated Apoptosis

Abstract

SUMMARY Plasminogen activator inhibitor-1 (PAI-1) paradoxically enhances tumor progression and angiogenesis, however the mechanism supporting this role is not known. Here we provide evidence that PAI-1 is essential to protect endothelial cells (EC) from FasL-mediated apoptosis. In the absence of host-derived PAI-1, human neuroblastoma cells implanted in PAI-1 deficient mice form smaller and poorly vascularized tumors containing an increased number of apoptotic EC cells. We observed that knockdown of PAI-1 in EC enhances cell-associated plasmin activity, and increases spontaneous apoptosis in vitro. We further demonstrate that plasmin cleaves FasL at Arg144 - Lys145, releasing from the surface of EC a soluble pro-apoptotic FasL fragment. The data provide a mechanism explaining the pro-angiogenic activity of PAI-1. SIGNIFICANCE PAI-1, the central regulator of plasmin generation is a predictor of poor clinical outcome in cancer patients. We previously reported that PAI-1 has a pro-angiogenic function but the mechanism has remained poorly understood. Here we describe a mechanism for the pro-angiogenic function of PAI-1 by providing evidence that PAI-1 protects EC from Fas/FasL-mediated apoptosis. We demonstrate that in the absence of PAI-1 in EC, there is an increase in plasmin generation and the release by plasmin of a soluble FasL fragment. This plasmin-generated soluble FasL activates Fas and is a potent inducer of apoptosis in EC. Our results suggest that PAI-1 could be a target for anti-angiogenic and anti-vascular therapies.

Notch signalling restricts inflammation and serpine1 expression in the dynamic endocardium of the regenerating zebrafish heart

“…8B). This could imply the involvement of Serpine1 in the maintenance of an initial activation state of the wound endocardium and is in line with its cellautonomous role in endothelial cells, regulating proliferation or apoptosis (Bajou et al, 2008). Further, we identify Notch as an important player during wound endocardium maturation (Fig.…”

Hyaluronic Acid Promotes Angiogenesis by Inducing RHAMM-TGFβ Receptor Interaction via CD44-PKCδ

“…4A), which confirmed that HA did not require VEGF to promote angiogenesis. PAI-1 protects endothelial cells from Fas-mediated apoptosis (Bajou et al, 2008), and facilitates retinal angiogenesis (Basu et al, 2009). These reports indicate the potential role of PAI-1 in angiogenesis.…”

SK-216, an Inhibitor of Plasminogen Activator Inhibitor-1, Limits Tumor Progression and Angiogenesis

“…Experiments using PAI-1-deficient (PAI-1 À/À ) mice have shown the significance of host PAI-1 in regulating tumor angiogenesis (11)(12)(13)(14). This process is thought to be mediated by the actions of PAI-1 on endothelial cells, thereby regulating plasmin-mediated proteolysis (15,16), modulating migration (17,18), and/or preventing apoptosis (19). PAI-1 is also known to be associated with cell motility.…”