biostudies-literatureKong XNHLBI NIH HHSNIGMS NIH HHSar95https://www.ebi.ac.uk/biostudies/studies/S-EPMC9582804biostudies-literatureUnknown33(11)Increased tension on VE-cadherin (VE-cad) complexes activates adaptive cell stiffening and local cytoskeletal reinforcement--two key signatures of intercellular mechanotransduction. Here we demonstrate that tugging on VE-cad receptors initiates a cascade that results in downstream integrin activation. The formation of new integrin adhesions potentiates vinculin and actin recruitment to mechanically reinforce stressed cadherin adhesions. This cascade differs from documented antagonistic effects of integrins on intercellular junctions. We identify focal adhesion kinase, Abl kinase, and RhoA GTPase as key components of the positive feedback loop. Results further show that a consequence of integrin involvement is the sensitization of intercellular force transduction to the extracellular matrixMolecular biology of the cellExtracellular matrix regulates force transduction at VE-cadherin junctions.PMC9582804R01 GM127554P01 HL060678Sullivan BKapustka ASchwarz GJLeckband DEKong XfalseExtracellular matrix regulates force transduction at VE-cadherin junctions.Increased tension on VE-cadherin (VE-cad) complexes activates adaptive cell stiffening and local cytoskeletal reinforcement--two key signatures of intercellular mechanotransduction. Here we demonstrate that tugging on VE-cad receptors initiates a cascade that results in downstream integrin activation. The formation of new integrin adhesions potentiates vinculin and actin recruitment to mechanically reinforce stressed cadherin adhesions. This cascade differs from documented antagonistic effects of integrins on intercellular junctions. We identify focal adhesion kinase, Abl kinase, and RhoA GTPase as key components of the positive feedback loop. Results further show that a consequence of integrin involvement is the sensitization of intercellular force transduction to the extracellular matrix2022-01-01T00:00:00Z2022 Sep2025-04-25T19:34:54.649Z2025-04-06T08:02:05.717ZS-EPMC95828043565329010.1091/mbc.E22-03-0075