Cécile Paques

PAI-1 mediates the antiangiogenic and profibrinolytic effects of 16K prolactin

The N-terminal fragment of prolactin (16K PRL) inhibits tumor growth by impairing angiogenesis, but the underlying mechanisms are unknown. Here, we found that 16K PRL binds the fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1), which is known to contextually promote tumor angiogenesis and growth. Loss of PAI-1 abrogated the antitumoral and antiangiogenic effects of 16K PRL. PAI-1 bound the ternary complex PAI-1–urokinase-type plasminogen activator (uPA)–uPA receptor (uPAR), thereby exerting antiangiogenic effects. By inhibiting the antifibrinolytic activity of PAI-1, 16K PRL also protected mice against thromboembolism and promoted arterial clot lysis. Thus, by signaling through the PAI-1–uPA–uPAR complex, 16K PRL impairs tumor vascularization and growth and, by inhibiting the antifibrinolytic activity of PAI-1, promotes thrombolysis.

The interaction of uPAR with VEGFR2 promotes VEGF-induced angiogenesis

uPAR enhances the internalization and thus the signaling downstream of a proangiogenic receptor. Helping a proangiogenic receptor Vascular endothelial growth factor (VEGF) induces the formation of new blood vessels, a process called angiogenesis, upon binding to VEGFR2, a cell surface receptor for which internalization enhances its ability to activate downstream effectors. Herkenne et al. found that in response to VEGF, another receptor called uPAR (urokinase plasminogen activator receptor) promoted an interaction between another receptor LRP-1 (low-density lipoprotein receptor–related protein 1), and VEGFR2, which led to VEGF2 internalization, thus enhancing the signal. Mice deficient in uPAR showed reduced VEGF-induced angiogenesis. Thus, treatments that disrupt the interaction between uPAR and VEGFR2 could be used to treat conditions in which angiogenesis is not desirable, such as in solid tumors or diabetic retinopathy. In endothelial cells, binding of vascular endothelial growth factor (VEGF) to the receptor VEGFR2 activates multiple signaling pathways that trigger processes such as proliferation, survival, and migration that are necessary for angiogenesis. VEGF-bound VEGFR2 becomes internalized, which is a key step in the proangiogenic signal. We showed that the urokinase plasminogen activator receptor (uPAR) interacted with VEGFR2 and described the mechanism by which this interaction mediated VEGF signaling and promoted angiogenesis. Knockdown of uPAR in human umbilical vein endothelial cells (HUVECs) impaired VEGFR2 signaling, and uPAR deficiency in mice prevented VEGF-induced angiogenesis. Upon exposure of HUVECs to VEGF, uPAR recruited the low-density lipoprotein receptor–related protein 1 (LRP-1) to VEGFR2, which induced VEGFR2 internalization. Thus, the uPAR-VEGFR2 interaction is crucial for VEGF signaling in endothelial cells.