PT  - JOURNAL ARTICLE
AU  - Caterina Ivaldo
AU  - Mario Passalacqua
AU  - Anna Lisa Furfaro
AU  - Cristina d’Abramo
AU  - Santiago Ruiz
AU  - Prodyot K. Chatterjee
AU  - Christine N. Metz
AU  - Mariapaola Nitti
AU  - Philippe Marambaud
TI  - Oxidative stress-induced MMP- and γ-secretase-dependent VE-cadherin processing is modulated by the proteasome and BMP9/10
AID  - 10.1101/2022.11.23.517709
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.11.23.517709
4099  - http://biorxiv.org/content/early/2022/11/24/2022.11.23.517709.short
4100  - http://biorxiv.org/content/early/2022/11/24/2022.11.23.517709.full
AB  - Classical cadherins, including vascular endothelial (VE)-cadherin, are targeted by matrix metalloproteinases (MMPs) and γ-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 γ-secretase in human umbilical endothelial cells (HUVECs). The cytoplasmic domain of VE-cadherin produced by γ-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 γ-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.Competing Interest StatementThe authors have declared no competing interest.A431Epidermoid carcinoma human cell lineAVMsArteriovenous MalformationsAJAdherens junctionsBMPBone Morphogenetic ProteinCTF1C-terminal fragment 1CTF2C-terminal fragment 2EPOXEpoxomicinFLFull LengthH2O2Hydrogen PeroxideHHTHereditary Hemorrhagic TelangiectasiaHUVECsHuman Umbilical Vein Endothelial CellsMMPsMatrix MetalloproteinasesOSOxidative stressTGFTransforming Growth FactorVE-cadherinVascular Endothelial Cadherin