Biology subjects

Ristori, T.

Publications and source records attributed to Ristori, T..

3 recordsLinked to original sources

bioRxiv2025

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

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.

systems biology↗

bioRxiv2025

Receptor stoichiometry predicts artery-typical vulnerability to altered Notch signaling during smooth muscle differentiation.

The development and maintenance of arterial smooth muscle cells (SMCs) rely on Jagged1-Notch2/Notch3 signaling. While Notch2 and Notch3 are thought to function redundantly during SMC development, clinical and experimental evidence suggests artery-specific importance for the two receptors. Combining in vitro, in vivo, and in silico models, we report that the canonical Notch signaling during SMC differentiation is largely driven by Notch2. While Notch2 and Notch3 co-regulate a large group of genes in SMCs upon Jagged1 interaction, Notch3 is a less potent inducer of Notch signaling than Notch2 and requires higher doses to potentiate a meaningful transcriptional response due to its weak interaction with RBPJ{kappa}. Consequently, Notch2 depletion abolishes Notch signaling in the SMCs of the large elastic arteries. However, high Jagged1 and Notch3 expression in smaller arteries like those in the brain can compensate for Notch2 loss. This work refines our mechanistic understanding of Notch signaling in the SMCs and offers region-specific insights into the Notch-related arterial diseases.

developmental biology↗

bioRxiv2023

Bmp9 regulates Notch signaling and the temporal dynamics of angiogenesis via Lunatic Fringe

In briefThe mechanisms regulating the signaling pathways involved in angiogenesis are not fully known. Ristori et al. show that Lunatic Fringe (LFng) mediates the crosstalk between Bone Morphogenic Protein 9 (Bmp9) and Notch signaling, thereby regulating the endothelial cell behavior and temporal dynamics of their identity during sprouting angiogenesis. HighlightsO_LIBmp9 upregulates the expression of LFng in endothelial cells. C_LIO_LILFng regulates the temporal dynamics of tip/stalk selection and rearrangement. C_LIO_LILFng indicated to play a role in hereditary hemorrhagic telangiectasia. C_LIO_LIBmp9 and LFng mediate the endothelial cell-pericyte crosstalk. C_LI Bone Morphogenic Protein 9 (Bmp9), whose signaling through Activin receptor-like kinase 1 (Alk1) is involved in several diseases, has been shown to independently activate Notch target genes in an additive fashion with canonical Notch signaling. Here, by integrating predictive computational modeling validated with experiments, we uncover that Bmp9 upregulates Lunatic Fringe (LFng) in endothelial cells (ECs), and thereby also regulates Notch activity in an inter-dependent, multiplicative fashion. Specifically, the Bmp9-upregulated LFng enhances Notch receptor activity creating a much stronger effect when Dll4 ligands are also present. During sprouting, this LFng regulation alters vessel branching by modulating the timing of EC phenotype selection and rearrangement. Our results further indicate that LFng can play a role in Bmp9-related diseases and in pericyte-driven vessel stabilization, since we find LFng contributes to Jag1 upregulation in Bmp9-stimulated ECs; thus, Bmp9-upregulated LFng results in not only enhanced EC Dll4-Notch1 activation, but also Jag1-Notch3 activation in pericytes.

developmental biology↗