Force-mediated recruitment and reprogramming of healthy endothelial cells drive vascular lesion growth

Apeksha Shapeti (), Jorge Barrasa-Fano, Abdel Rahman Abdel Fattah, Janne Jong, José Antonio Sanz-Herrera, Mylène Pezet, Said Assou, Emilie Vet, Seyed Ali Elahi, Adrian Ranga, Eva Faurobert () and Hans Oosterwyck ()
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Apeksha Shapeti: Biomechanics section
Jorge Barrasa-Fano: Biomechanics section
Abdel Rahman Abdel Fattah: Biomechanics section
Janne Jong: Biomechanics section
José Antonio Sanz-Herrera: Universidad de Sevilla
Mylène Pezet: Institute for Advanced Biosciences
Said Assou: CHU Montpellier
Emilie Vet: Biomechanics section
Seyed Ali Elahi: Biomechanics section
Adrian Ranga: Biomechanics section
Eva Faurobert: Institute for Advanced Biosciences
Hans Oosterwyck: Biomechanics section

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Force-driven cellular interactions are crucial for cancer cell invasion but remain underexplored in vascular abnormalities. Cerebral cavernous malformations (CCM), a vascular abnormality characterized by leaky vessels, involves CCM mutant cells recruiting wild-type endothelial cells to form and expand mosaic lesions. The mechanisms behind this recruitment remain poorly understood. Here, we use an in-vitro model of angiogenic invasion with traction force microscopy to reveal that hyper-angiogenic Ccm2-silenced endothelial cells enhance angiogenic invasion of neighboring wild-type cells through force and extracellular matrix-guided mechanisms. We demonstrate that mechanically hyperactive CCM2-silenced tips guide wild-type cells by transmitting pulling forces and by creating paths in the matrix, in a ROCKs-dependent manner. This is associated with reinforcement of β1 integrin and actin cytoskeleton in wild-type cells. Further, wild-type cells are reprogrammed into stalk cells and activate matrisome and DNA replication programs, thereby initiating proliferation. Our findings reveal how CCM2 mutants hijack wild-type cell functions to fuel lesion growth, providing insight into the etiology of vascular malformations. By integrating biophysical and molecular techniques, we offer tools for studying cell mechanics in tissue heterogeneity and disease progression.

Date: 2024
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DOI: 10.1038/s41467-024-52866-6

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