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.

1 The effect of adenosine 5'-triphosphate (ATP) on the free cytosolic Ca2l concentration ([Ca2"] The ATP-induced relaxation of the K+-prestimulated preparations was not inhibited by 8-phenyltheophylline, a potent P,-purinoceptor antagonist. 7 The order of potency for relaxation of the ATP analogues was 2-MeSATP>ATP>fyMe-ATP, which is characteristic for P4,-purinoceptors. 8 These results indicate that, besides its activating effect, ATP also relaxes the mouse urinary bladder.It is suggested that the relaxant effect, mediated through P2y-purinoceptors, is mainly responsible for the low contractile potency of ATP in the bladder.

uPAR enhances the internalization and thus the signaling downstream of a proangiogenic receptor.

The recruitment of pericytes and vascular smooth muscle cells (SMCs) that enwrap endothelial cells (ECs) is a crucial process for vascular maturation and stabilization. Communication between these two cell types is crucial during vascular development and in maintaining vessel homeostasis. Extracellular vesicles (EVs) have emerged as a new communication tool involving the exchange of microRNAs between cells. In the present study, we searched for microRNAs that could be transferred via EVs from ECs to SMCs and vice versa. Thanks to a microRNA profiling experiment, we found that two microRNAs are more exported in each cell type in coculture experiments: while miR-539 is more secreted by ECs, miR-582 is more present in EVs from SMCs. Functional assays revealed that both microRNAs can modulate both cell-type phenotypes. We further identified miR-539 and miR-582 targets, in agreement with their respective cell functions. The results obtained in vivo in the neovascularization model suggest that miR-539 and miR-582 might cooperate to trigger the process of blood vessel coverage by smooth muscle cells in a mature plexus. Taken together, these results are the first to highlight the role of miR-539 and miR-582 in angiogenesis and communication between ECs and SMCs.

In the version of the cover caption initially published, the definitions of the green and blue staining were reversed. Green represents nuclear staining, and blue represents the apical membrane. The error has been corrected in the HTML version of the caption. CO R R I G E N DA A N D E R R ATANATURE MEDICINE VOLUME 21 | NUMBER 5 | MAY 2015 537