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bioRxiv · 10.1101/2025.09.26.678712

Targeting stiffness-dependent YAP/TAZ restores angiogenesis dynamics impaired by ALK1 knockout in silico

Passier, M.·Loerakker, S.·Ristori, T.
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Abstract

Hereditary Hemorrhagic Telangiectasia (HHT) is a currently uncurable genetic disorder caused by loss-of-function mutations in the ALK1-BMP9 pathway, leading to dysregulated angiogenesis and consequential vascular malformations. Recent experiments also implicate the mechanotransducers YAP/TAZ in HHT pathology. However, how YAP/TAZ stiffness sensitivity and signaling activity contribute to aberrant HHT angiogenesis remains poorly understood. Here, we extended our previous computational framework of stiffness-mediated YAP/TAZ-VEGF-NOTCH crosstalk to account for ALK1 signalling and predict the resulting angiogenic temporal dynamics. Our simulations predicted that ALK1 knockout impairs NOTCH activation, slowing endothelial phenotypic selection and shuffling while enhancing filopodia activity, features corresponding with hypersprouting. These effects were most pronounced in low stiffness environments, consistent with the previously observed prevalence of HHT vascular malformations in low stiffness organs. Importantly, the temporal dynamics of endothelial phenotypic selection and shuffling, as well as key protein activity levels, were partially restored by direct or cytoskeleton-mediated inhibition of YAP/TAZ resulting from increased NOTCH activation. These computational findings offer more mechanistic insight into the signalling pathways and temporal dynamics of endothelial phenotypic selection underlying HHT vascular anomalies, and suggest that targeting YAP/TAZ and endothelial stiffness sensitivity may offer a promising therapeutic strategy to restore physiological angiogenesis. Author SummaryMechanical cues such as extracellular matrix stiffness, sensed by endothelial cells lining blood vessels, play a critical role in angiogenesis, the process of blood vessel formation from pre-existing vessels. Understanding the impact of these cues on angiogenesis in health and in diseased conditions could help guide new treatments for angiogenesis-related disorders, such as Hereditary Hemorrhagic Telangiectasia (HHT). In HHT, genetic mutations disrupt normal vessel development, leading to malformations that can rupture and have detrimental consequences. Here, we developed a computational model to investigate the effects of HHT-associated genetic mutations on angiogenic signaling of endothelial cells exposed to different stiffnesses. Simulations predicted that the mutation impairs endothelial phenotypic selection and shuffling, necessary for physiological angiogenesis. The mutation effects to be largest in soft organs and identified the mechanotransducers YAP/TAZ as possible targets to restore physiological signaling. Therefore, with this model, we have created a platform to simulate endothelial cell behavior in HHT patients, allowing us to explore mechanosensitive pathways as potential targets potentially extending future treatment options.

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Passier, M., Loerakker, S., Ristori, T.. 2025-09-29. Targeting stiffness-dependent YAP/TAZ restores angiogenesis dynamics impaired by ALK1 knockout in silico. https://doi.org/10.1101/2025.09.26.678712

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