New Soluble Angiopoietin Analog of Hepta-ANG1 Prevents Pathological Vascular Leakage.,Biotechnology and Bioengineering

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New Soluble Angiopoietin Analog of Hepta-ANG1 Prevents Pathological Vascular Leakage.
Biotechnology and Bioengineering ( IF 3.5 ) Pub Date : 2020-09-24 , DOI: 10.1002/bit.27580
Pan Liu ₁ , Michael Ryczko ₂ , Xinfang Xie _{1,

3} , Jason Baardsnes ₄ , Simon Lord-Dufour ₄ , Yves Duroche ₄ , Emily Anne Hicks ₅ , Aftab Taiyab ₅ , Heather Sheardown ₅ , Susan E Quaggin ₁ , Jing Jin ₁

Affiliation

Vascular leak is a key driver of organ injury in diseases, and strategies that reduce enhanced permeability and vascular inflammation are promising therapeutic targets. Activation of the angiopoietin‐1 (ANG1)‐Tie2 tyrosine kinase signaling pathway is an important regulator of vascular quiescence. Here we describe the design and construction of a new soluble ANG1 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 ANG1 with a heptameric scaffold derived from the C‐terminus of serum complement protein C4‐binding protein α. We refer to this new fusion protein biologic as Hepta‐ANG1, which forms a stable heptamer and induces Tie2 phosphorylation in cultured cells, and in the lung following intravenous injection of mice. Injection of Hepta‐ANG1 ameliorates vascular endothelial growth factor‐ and lipopolysaccharide‐induced vascular leakage, in keeping with the known functions of Angpt1‐Tie2 in maintaining quiescent vascular stability. The new Hepta‐ANG1 fusion is easy to produce and displays remarkable stability with high multimericity that can potently activate Tie2. It could be a new candidate ANG1 mimetic therapy for treatments of inflammatory vascular leak, such as acute respiratory distress syndrome and sepsis.

中文翻译：

Hepta-ANG1 的新型可溶性血管生成素类似物可预防病理性血管渗漏。

血管渗漏是疾病中器官损伤的关键驱动因素，降低渗透性增强和血管炎症的策略是有希望的治疗靶点。血管生成素-1 (ANG1)-Tie2 酪氨酸激酶信号通路的激活是血管静止的重要调节因子。在这里，我们描述了一种新的可溶性 ANG1 模拟物的设计和构建，该模拟物是体外和体内内皮 Tie2 的有效激活剂。使用嵌合融合策略，我们将 ANG1 的细胞外基质 (ECM) 结合和寡聚化结构域替换为源自血清补体蛋白 C4 结合蛋白 α C 端的七聚体支架。我们将这种新的融合蛋白生物称为 Hepta-ANG1，它形成稳定的七聚体并在培养细胞中诱导 Tie2 磷酸化，并在小鼠静脉注射后的肺中。注射 Hepta-ANG1 可改善血管内皮生长因子和脂多糖诱导的血管渗漏，这与 Angpt1-Tie2 在维持静止血管稳定性方面的已知功能一致。新的 Hepta-ANG1 融合很容易产生，并显示出显着的稳定性和高度的多聚性，可以有效地激活 Tie2。它可能是一种新的候选 ANG1 模拟疗法，用于治疗炎症性血管渗漏，例如急性呼吸窘迫综合征和败血症。新的 Hepta-ANG1 融合很容易产生，并显示出显着的稳定性和高度的多聚性，可以有效地激活 Tie2。它可能是一种新的候选 ANG1 模拟疗法，用于治疗炎症性血管渗漏，例如急性呼吸窘迫综合征和败血症。新的 Hepta-ANG1 融合很容易产生，并显示出显着的稳定性和高度的多聚性，可以有效地激活 Tie2。它可能是一种新的候选 ANG1 模拟疗法，用于治疗炎症性血管渗漏，例如急性呼吸窘迫综合征和败血症。

更新日期：2020-09-24

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