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bioRxiv · 10.1101/2020.03.30.016147

New Soluble Angiopoietin Analog of C4BP-ANG1 Prevents Pathological Vascular Leakage

Liu, P.·Ryczko, M.·Xie, X.·Taiyab, A.·Sheardown, H.·Quaggin, S. E.·Jin, J.
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Abstract

Vascular leak is a key driver of organ injury in diseases such as Acute Respiratory Distress Syndrome caused by viruses, including COVID-19. Strategies that reduce enhanced permeability and vascular inflammation are promising therapeutic targets. Activation of the Angiopoietin-1 (Angpt1)-Tie2 tyrosine kinase signaling pathway is an important regulator of vascular quiescence. Here we describe the design and construction of a new soluble ANGPT1 mimetic that is a potent activator of endothelial Tie2 in vitro and in vivo. Using a chimeric fusion strategy, we replaced the extracellular matrix (ECM) binding and oligomerization domain of ANGPT1 with a heptameric scaffold derived from the C-terminus of serum complement protein C4-binding protein (C4BP). We refer to this new fusion protein biologic as C4BP-ANG1, which forms a stable heptamer and induces TIE2 phosphorylation in cultured cells, and in the lung following i.v. injection of mice. Injection of C4BP-ANG1 ameliorates VEGF- and lipopolysaccharide-induced vascular leakage, in keeping with the known functions of Angpt1-Tie2 in maintaining quiescent vascular stability, and therefore is a promising candidate treatment for inflammatory endothelial dysfunction.

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Liu, P., Ryczko, M., Xie, X., Taiyab, A., Sheardown, H., Quaggin, S. E., Jin, J.. 2020-04-01. New Soluble Angiopoietin Analog of C4BP-ANG1 Prevents Pathological Vascular Leakage. https://doi.org/10.1101/2020.03.30.016147

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