Biology subjects

Virtanen, N.

Publications and source records attributed to Virtanen, N..

5 recordsLinked to original sources

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↗

bioRxiv2025

Mechanosensitive interactions between Jag1 and Myo1c control Jag1 trafficking in endothelial cells

Morphogenesis of the cardiovascular system is responsive to hemodynamic cues. In endothelial cells the organization of morphogenic signaling proteins can be regulated by membrane presentation and internalization of proteins. How these signaling proteins are regulated by hemodynamics is unclear. One of the signaling proteins that is regulated by hemodynamics is Jagged1, a ligand in the Notch pathway. Here we set out to identify factors that differentially interact with Jagged1 in response to shear stress exposure, by combining an orbital shaker as a shear stress platform with endothelial cells expressing Jagged1 coupled to an APEX2-tag for proximity labeling. Myo1c was identified and confirmed through coimmunoprecipitation as a Jag1 interacting factor under static conditions, with reduced interaction after exposure to shear in endothelial cells. We showed that Jagged1 polarized downstream of shear followed by nucleograde transport of Jagged1. Myo1c knockout inhibited shear-induced Jagged1 polarization and consequent nucleograde transport. Further, Myo1c knockdown reduced membrane levels of Jagged1 under static conditions, but not under shear conditions. Together, our data reveal a role for Myo1c in the hemodynamic control of Jagged1 localization in endothelial cells.

cell biology↗

bioRxiv2024

Jagged1 is a Notch-independent mechanotransducer in endothelial cells

The Notch signaling pathway plays a crucial role in regulating endothelial biology. Notch signaling is sensitive to hemodynamic forces and governs mechanically-driven cardiovascular development, physiology, and remodeling. However, the mechanisms by which mechanical forces integrate with the Notch pathway remain largely unknown. Here, we uncover a non-canonical role for the Notch ligand Jagged1 in regulating the activity of mechanosensitive kinases in endothelial cells. We show that stress induces expression and relocalization of Jagged1 to cell junctions downstream of flow. Jagged1 expression under stress demonstrates magnitude dependence and peaks at 0.8-1Pa without impacting Jagged1s Notch-activation potential. On the contrary Jagged1 regulates the activity of mechanosensitive kinases. Deletion of Jagged1 reduces the activity of VEGFR2 and ERK in vitro and diminished ERK activity in zebrafish embryos without affecting canonical Notch signaling. Furthermore, the direct physical stimulation of Jagged1 using antibody-conjugated beads triggers the activation of VEGFR2 and ERK, mediated by Jagged1-induces Src activation. Taken together, we demonstrate a novel non-canonical role for Jagged1 as a regulator of the activity of pathways involved in endothelial mechanotransduction.

cell biology↗

bioRxiv2024

Heat stress sensitizes zebrafish embryos to neurological and cardiac toxicity.

Global warming increases the risk of dangerous heat waves, which may have deleterious effects on humans and wildlife. Here, we have utilized zebrafish embryos as a model to analyse heat stress and effect of chemical compounds on responses to heat stress. The temperature adaptation limit of zebrafish embryos was 37{degrees}C in behavioural test and 38{degrees}C in cardiac test. Polyaromatic hydrocarbon phenanthrene completely blocked the behavioural adaptation to heat stress. Interestingly, the cardiotoxic effects of lapatinib, phenanthrene and paclitaxel were induced by heat stress. Taken together, our data indicates that motility and cardiac function of zebrafish embryos can be utilized as a model to analyze modulatory effects of compounds on heat stress. HighlightsO_LIZebrafish embryos can be utilized as an in vivo model for acute heat stress C_LIO_LIPhenanthrene inhibited motility increase upon heat stress C_LIO_LICardiotoxicity of lapatinib, paclitaxel and phenanthrene was potentiated by heat stress C_LI

pharmacology and toxicology↗

bioRxiv2024

Phosphoproteomic analysis reveals the diversity of signaling behind ErbB inhibitor-induced phenotypes

The impact of kinase inhibitors on the phosphoproteome has been rarely investigated at a whole organism level. Here we performed a phosphoproteomic analysis in embryonic zebrafish to identify the signaling pathways perturbed by ErbB receptor tyrosine kinase inhibitors at the organism level. The phosphorylation of proteins associated with the PI3K/Akt, p38 MAPK, Notch, Hippo/Yap and {beta}-catenin signaling pathways were differentially regulated by the ErbB inhibitors. Gene set enrichment analyses indicated differential neurological and myocardial phenotypes of different ErbB inhibitors. To assess the neurological and myocardial effects, motility and ventricle growth assays were performed on zebrafish embryos treated with the ErbB and downstream signaling pathway inhibitors. The treatment with the inhibitors targeting the PI3K/Akt, p38 MAPK, and Notch signaling pathways along with the ErbB inhibitors AG1478 and Lapatinib perturbed the overall movement and ventricle wall growth of zebrafish embryos. Taken together, these results indicate that inhibitors with the same primary targets can affect different signaling pathways while eliciting similar physiological phenotypes.

cell biology↗