New soluble angiopoietin analog of Hepta‐ANG1 prevents pathological vascular leakage

Abstract

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 C4binding 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.

Insight into the Role of Angiopoietins in Ageing-Associated Diseases

“…Future investigations in endothelial Ang-TIE signaling may also unravel the molecular mechanisms underlying multiple organ dysfunctions and multimorbidity in AADs [101]. Moreover, biologics targeting to Ang1-TIE2 pathway may be applied to the high fatality rate of the latest global crisis, COVID-19 infection and its comorbidities, involving acute respiratory distress syndrome, cardiovascular diseases, obesity and diabetes [102][103][104][105][106].…”

Activation of Angiopoietin-Tie2 Signaling Protects the Kidney from Ischemic Injury by Modulation of Endothelial-Specific Pathways

“…To advance clinical application of Tie2 activation to treat patients with IR-AKI, we tested a new ANGPT1 mimetic known as Hepta-ANG1 that is long-acting, nontoxic, and robustly activates Tie2 in vivo . 34 When administered as a single dose through intraperitoneal injection to adult mice, Hepta-ANG1 activated Tie2 and downstream Akt signaling in the kidney and other tissues (Figure 3, A–D). Given the difference observed at 24 hours in creatinine elevation in the VE-PTPiKO model, we chose this early time point to harvest kidneys to identify acute effects of Tie2 activation after Hepta-ANG1 administration.…”

Value of Serum miR-34a and Ang-1 in Severity Evaluation and Prognosis of Neonatal Respiratory Distress Syndrome

“…In previous studies, the downregulation of Ang-1 expression was responsible for the decreased stability and increased permeability of pulmonary capillary endothelial cells in patients with ARDS [ 17 ]. The main reason was that Ang-1 could not only reduce the synthesis of nitric oxide (NO) by degrading bradykinin but also promote the generation of oxygen free radicals induced by oxidative stress to increase the decomposition of NO and aggravate the damage of pulmonary vascular endothelial cells [ 18 ]. NCIS score is a domestic neonatal critical illness score method, which is mainly used to analyze and observe blood gas analysis, vital signs, biochemical tests, and other indicators of children [ 19 ].…”