Angiogenesis induced by signal transducer and activator of transcription 5A (STAT5A) is dependent on autocrine activity of proliferin.

Multiple secreted factors induce the formation of new blood vessels (angiogenesis). The signal transduction events that orchestrate the numerous cellular activities required for angiogenesis remain incompletely understood. We have shown previously that plays a pivotal role in angiogenesis induced by FGF2 and FGF8b. To delineate the signaling pathway downstream of we expressed constitutively active (CA) or dominant-negative (DN) mutant in mouse brain endothelial cells (EC). We found that the conditioned medium from but not from dominant-negative duanyu18135A overexpressing EC is sufficient to induce EC invasion and tube formation, indicating that duanyu18135A regulates the secretion of autocrine proangiogenic factors. Conversely, conditioned medium had no effect on EC proliferation. Using a comparative genome-wide transcription array screen, we identified the prolactin family member proliferin (PLF1 and PLF4) as a candidate autocrine factor. The transcription and secretion of PLF by EC was confirmed by quantitative RT-PCR and Western blotting, respectively. CA-duanyu18135A binds to the PLF1 promoter region, suggesting a direct transcriptional regulation. Knockdown of PLF expression by shRNA or by blocking of PLF activity with neutralizing antibodies removed the CA-duanyu18135A-dependent proangiogenic activity from the conditioned medium of EC. Similarly, the ability of concentrated conditioned medium from CA-duanyu18135A transfected EC to induce angiogenesis in Matrigel plugs in vivo was abolished when PLF was depleted from the medium. These observations demonstrate a signaling cascade in EC and implicate PLF as autocrine regulator of EC invasion and tube formation.

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