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bioRxiv · 10.1101/2024.09.26.615054

Plasminogen Activator Inhibitor-1 is internalized by endothelial cells via macropinocytosis to evade degradation

McAdow, M. E.·Ahmetaj, G.·Hauschel, R.·Eichmann, A.·Sessa, B. E.
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Abstract

Plasminogen activator inhibitor1 (PAI1) promotes hemostasis and is a biomarker of cardiovascular disease but accumulating evidence supports a role for PAI1 in intracellular biology. Recently, we found that PAI1 directly inhibits endothelial nitric oxide synthase (eNOS) and that exogenous PAI1 is internalized and traffics to eNOS. However, prior work has demonstrated that when PAI1 is internalized via LRP1 and uPAR on the cell surface and is internalized and degraded. Our objective was to identify the mechanism by which PAI1 is internalized and evades degradation. Here, we show that PAI1 is internalized by endothelial cells in an energy-dependent manner and persists in the cell for at least 6 hours. Entry is independent of LRP1, uPAR, or clathrin-mediated endocytosis. It is internalized in large vesicles, is inhibited by amiloride and nocodazole, and is partially dependent on CDC42, consistent with macropinocytosis. We propose that following internalization by macropinocytosis, PAI1 evades degradation, permitting eNOS inhibition.

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McAdow, M. E., Ahmetaj, G., Hauschel, R., Eichmann, A., Sessa, B. E.. 2024-09-26. Plasminogen Activator Inhibitor-1 is internalized by endothelial cells via macropinocytosis to evade degradation. https://doi.org/10.1101/2024.09.26.615054

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