The pro‐ or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent

Abstract

Plasminogen activator inhibitor 1 (PAI-1) is believed to control proteolytic activity and cell migration during angiogenesis. We previously demonstrated in vivo that this inhibitor is necessary for optimal tumor invasion and vascularization. We also showed that PAI-1 angiogenic activity is associated with its control of plasminogen activation but not with the regulation of cell-matrix interaction. To dissect the role of the various components of the plasminogen activation system during angiogenesis, we have adapted the aortic ring assay to use vessels from gene-inactivated mice. The single deficiency of tPA, uPA, or uPAR, as well as combined deficiencies of uPA and tPA, did not dramatically affect microvessel formation. Deficiency of plasminogen delayed microvessel outgrowth. Lack of PAI-1 completely abolished angiogenesis, demonstrating its importance in the control of plasmin-mediated proteolysis. Microvessel outgrowth from PAI-1-/- aortic rings could be restored by adding exogenous PAI-1 (wild-type serum or purified recombinant PAI-1). Addition of recombinant PAI-1 led to a bell-shaped angiogenic response clearly showing that PAI-1 is proangiogenic at physiological concentrations and antiangiogenic at higher levels. Using specific PAI-1 mutants, we could demonstrate that PAI-1 promotes angiogenesis at physiological (nanomolar) concentrations through its antiproteolytic activity rather than by interacting with vitronectin.

Role of plasminogen activator-plasmin system in tumor angiogenesis

“…Furthermore, these in vivo observations are amply supported by results obtained in vitro in the mouse aortic ring model [96]. The essential role of PAI-1 in angiogenesis may be explained by the multifunctional nature of PAI-1 (see above).…”

“…In the aortic ring assay, no vessels form from PAI-1-deficient animals. Addition of exogenous recombinant PAI-1 at a physiological concentration restores microvessel sprouting, while at 'therapeutical' concentrations, angiogenesis is inhibited [96]. Similarly, PAI-1 inhibits bFGF-induced angiogenesis when added at high concentrations [98].…”

“…Since cellular migration is considered to result from a succession of attachment and detachment events, this effect of PAI-1 would lead to a migratory phenotype. To address the mechanism of action of PAI-1, adenoviruses were used to deliver two mutant forms of PAI-1 to PAI-1 -deficient mice in the transplantation system mentioned above [92] and in the aortic ring assay [96]. The PAI-1 mutants either (i) bind vitronectin normally but fail to inhibit uPA or tPA or (ii) inhibit PAs normally but have negligible binding to vitronectin.…”

Independent prognostic value of angiogenesis and the level of plasminogen activator inhibitor type 1 in breast cancer patients

“…Accordingly, it has been reported that tumour angiogenesis is drastically impaired in mice with targeted disruption of the PAI-1 gene (Bajou et al, 1998. A few other model system studies have also suggested a proangiogenic role of PAI-1 (Lambert et al, 2001;McMahon et al, 2001;Devy et al, 2002). In particular, the possible role of uPA and PAI-1 in angiogenesis was of interest in the preparation of the present study.…”

“…In several cell culture and animal model systems, PAI-1 has been found to have a proangiogenic effect (Bajou et al, 1998Lambert et al, 2001;McMahon et al, 2001;Devy et al, 2002). However, the clinical significance of the biological interaction of angiogenesis and the plasminogen activator system is unknown.…”