Insight into the Role of Angiopoietins in Ageing-Associated Diseases

Figures

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  Figure 1. Correlation between vascular endothelial cells (ECs) and ageing-associated diseases (AADs). The schema illustrates the hypothesis that endothelial dysfunction and/or unsuitable activation appear as the forerunners of AADs, such as atherosclerosis, type 2 diabetes, chronic kidney disease (CKD), cardiovascular diseases, Alzheimer’s disease (AD) and cancer. Normal ageing also correlates with functional and phenotypic changes of ECs.

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  Figure 2. Angiopoietin–TIE signaling pathway in the vascular endothelium. (a) The schema indicates Ang-TIE signaling in vascular ECs. Ang1 promotes endothelial cell survival, vessel stability and barrier function via activation of signaling receptor TIE2 and its downstream targets, PI3K/AKT and Rho family GTPases. Ang1-TIE2-PI3K/AKT signaling inhibits NF-kB, FOXO 1 and FOXO 1-induced Ang2. Ang2 is a weak agonist or antagonist which modulates Ang1-TIE2 pathway. Upon inflammation and vascular injury, Ang2, stored in Weibel-Palade bodies, are released in circulation, antagonizes Ang1-TIE2 signaling and then increases FOXO1 and Ang2. Unlike signaling receptor TIE2, TIE1 is an orphan receptor homolog of TIE2, and mostly does not react to ligands. In some cases, TIE2 signaling is stimulated by phosphorylation due in part to the TIE receptor complex with TIE1. TIE2 activation is also achieved by the inhibition of a VE-PTP, which dephosphorylates and deactivates TIE2. Note that ‘P’ next to the intracellular part of TIE2 indicates phosphorylation. (b) The left upper panel shows transmission EM images with schematic indication of vascular ECs and pericytes. The right upper panel indicates that…

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  Figure 3. Ang-TIE therapeutics against diabetic retinal diseases. The schema indicates possible Ang-TIE targeting drugs for diabetic retinal diseases and their signaling targets in ECs. Faricimab, a bispecific antibody that targets both Ang2 and VEGF-A, is in phase 3 clinical trials for diabetic retinal diseases, such as diabetic macular edema (DME). VE-PTP inhibitors, ARP-1536 and AKB-9778, which can activate the Ang1-TIE2 pathway, are under clinical development for DME. In addition, VE-PTP inhibition by those drugs deactivate VEGFR2. In a phase 2a clinical trial, AKB-9778 with ranibizumab, a recombinant VEGF-A antibody, resulted in significant reduction in DME. A collagen IV-derived peptide, ATX107, is under clinical development. ATX107 uniquely converted Ang2 into a TIE2 agonist, and thereby activating TIE2 signaling in experimental models. ATX107 also inhibited VEGF signaling. In experimental models of diabetes, soluble Ang1 variant, COMP-Ang1, protected retinal vascular structure, blood retinal barrier integrity, and visual dysfunction.