Ivaldo, C. | Search bioRxiv

bioRxiv2025

An angiopoietin-2 vaccine improves arteriovenous malformation pathology in hereditary hemorrhagic telangiectasia mice

Hereditary hemorrhagic telangiectasia (HHT) is a genetic vascular disorder that causes systemic arteriovenous malformations (AVMs) associated with severe complications. Angiopoietin (ANG)-2 has been identified as a consistently upregulated secreted protein across various HHT models, and neutralizing ANG2 reduces AVMs in mice. ANG2 has thus emerged as a potential target for HHT treatment. Here, we report the development of a peptide vaccine (ANG2-P3:CRM197) that selectively targets ANG2 over ANG1 and tested its effectiveness in decreasing retinal AVMs in neonatal mice injected with BMP9/10 blocking antibodies, a model of HHT. Litter groups from female C57BL/6 mice immunized with ANG2-P3:CRM197 received injections of anti-BMP9/10 antibodies, and their retinas were examined for vascular pathology. The potential toxicity of the vaccine was evaluated in females 12 months post-immunization through echocardiography, basic metabolic panels, and lipid profiles. Circulating anti-ANG2 antibodies were detected in nursing neonates of vaccinated females, with antibody levels comparable between litters and their dams, indicating effective antibody transfer from the dams. A significant decrease in AVM number and size was observed in the retinas of pups exposed to ANG2-P3:CRM197 antibodies compared to unexposed pups. Arterial and venous diameters were normalized in the vaccinated pups retinas. The vaccinated females showed no abnormalities in cardiac, liver, or kidney functions. A vaccine strategy targeting ANG2 appears safe and improves AVM pathology in HHT mice. These findings further support the potential of inhibiting ANG2 as a viable approach for treating AVMs in HHT. KEY POINTSO_LIA peptide vaccine that targets ANG2 reduced AVM number and size, and normalized arterial and venous diameters in a mouse model of HHT. C_LIO_LIThe vaccine did not cause any abnormalities in cardiac, liver, or kidney functions, and thus appeared safe. C_LI

cell biology↗

bioRxiv2022

Oxidative stress-induced MMP- and γ-secretase-dependent VE-cadherin processing is modulated by the proteasome and BMP9/10

Classical cadherins, including vascular endothelial (VE)-cadherin, are targeted by matrix metalloproteinases (MMPs) and {gamma}-secretase during adherens junction (AJ) disassembly, a mechanism that might have relevance for endothelial cell (EC) integrity and vascular homeostasis. Here, we show that oxidative stress triggered by H2O2 exposure induced efficient VE-cadherin proteolysis by MMPs and {gamma}-secretase in human umbilical endothelial cells (HUVECs). The cytoplasmic domain of VE-cadherin produced by {gamma}-secretase, VE-Cad/CTF2 - a fragment that has eluded identification so far - could readily be detected after H2O2 treatment. VE-Cad/CTF2, released into the cytosol, was tightly regulated by proteasomal degradation and was sequentially produced from an ADAM10/17-generated C-terminal fragment, VE-Cad/CTF1. Interestingly, BMP9 and BMP10, two circulating ligands critically involved in vascular maintenance, significantly reduced VE-Cad/CTF2 levels during H2O2 challenge, as well as mitigated H2O2-mediated actin cytoskeleton disassembly during VE-cadherin processing. Notably, BMP9/10 pretreatments efficiently reduced apoptosis induced by H2O2, favoring endothelial cell recovery. Thus, oxidative stress is a trigger of MMP- and {gamma}-secretase-mediated endoproteolysis of VE-cadherin and AJ disassembly from the cytoskeleton in ECs, a mechanism that is negatively controlled by the EC quiescence factors, BMP9 and BMP10.

cell biology↗