Biology subjects

Odenthal-Schnittler, M.

Publications and source records attributed to Odenthal-Schnittler, M..

4 recordsLinked to original sources

bioRxiv2025

A critical role for VE-cadherin in regulating actin dynamics during endothelial maturation and non-inflammatory activation via a tension-sensitive intermediate state

Epithelial and endothelial monolayers maintain homeostasis by adapting to physiological stimuli and injury through conversion processes that remain incompletely understood. Using endothelial cell cultures (HUVEC), we investigate how monolayer maturation and non-inflammatory remodeling are molecularly regulated. Maturation involves reduced cell perimeter causing increased junctional VE-cadherin, which recruits junctional actin and integrins, establishing a quiescent, stable monolayer. Remarkably, we identify a previously unrecognized, rapid and reversible intermediate-state, marked by VE-cadherin linearization and actomyosin relaxation via MLC-dephosphorylation, that emerges during non-inflammatory activation triggered by onset or increase in shear stress. This novel intermediate-state enhances junctional actin and integrin recruitment, strengthening barrier-function while protecting endothelial cells from overstimulation and mechanical damage. Re-phosphorylation of MLC dissolves junctional actin and induces formation of junction-associated-intermittent-lamellipodia (JAIL), enabling cell shape change and arterial phenotype conversion. Overall, loss of actomyosin tension and junctional VE-cadherin-concentration defines actin recruitment and reveals a tension-sensitive, cell-protective intermediate state that primes endothelial remodeling, offering an expanded model for mechano-transduction and shear stress adaptation.

cell biology↗

bioRxiv2025

TNF-a induces VE-cadherin-dependent gap/JAIL cycling through an intermediate state essential for neutrophil transmigration

Inflammatory endothelial phenotypes describe distinct cellular patterns essential for controlling transendothelial migration of leukocytes (TEM). While TNF--induced CAM expression mediates leukocyte interaction, the role of a potential inflammatory morphological phenotype (IMP) - characterised by barrier-function decrease and shape-change in TEM - remains unclear. This study identifies the TNF--induced IMP as indispensable for neutrophil TEM, while regulating barrier-function. The TNF--induced IMP progresses through two states: an intermediate state that transiently enhances barrier function via MLC-dephosphorylation, junctional actin recruitment and VE-cadherin linearisation, protecting the monolayer from collapse; while the subsequent development of the IMP requires MLC rephosphorylation, junctional actin disassembly, stress fibre formation and Arp2/3-mediated membrane protrusions causing shape-change. This in turn dilutes junctional VE-cadherin, forming intercellular gaps for neutrophil TEM, while inducing junction-associated intermittent lamellipodia (JAIL) to locally restore VE-cadherin adhesion, appearing as gap/JAIL cycles driving junctional dynamics. VE-cadherin overexpression blocks TNF--induced IMP and gap/JAIL cycling, reducing TEM by [~]80% without altering CAM expression. These findings highlight gap/JAIL cycling and MLC phosphorylation as key IMP regulators and potential therapeutic targets for inflammatory diseases.

immunology↗

bioRxiv2024

Mechanical Strain Activates Planar Cell Polarity Signaling to Coordinate Vascular Cell Dynamics

Mechanical stimuli, particularly laminar blood flow, play a crucial role in shaping the vascular system. Changes in the rate of blood flow manifest in altered shear stress, which activates signaling cascades that drive vascular remodeling. Consistently, dysregulation of the endothelial response to fluid shear forces and aberrant flow patterns both lead to pathological conditions, including impaired blood vessel development and atherosclerosis. Despite its importance, the mechanisms driving the coordinated cell behavior underlying vascular remodeling are not fully understood. Combining classical cell biological approaches with advanced image analysis, mathematical modeling, biomimetic strategies, and in vivo studies, we identify the planar cell polarity (PCP) protein Vangl1 as an enforcer of flow-dependent cell dynamics in the vascular system. We demonstrate that shear stress triggers the relocation of Vangl1 from an internal reservoir to the plasma membrane at the initiation of cell remodeling. Membrane enrichment of Vangl1 is mediated by a Coronin1C-dependent shift in the equilibrium between endo- and exocytosis and results in the spatial reorganization of another essential PCP protein, Frizzled6 (Fzd6). The resulting mutual exclusion of the core PCP proteins Fzd6 and Vangl1 augments differential junctional and cytoskeletal dynamics along the flow axis. Loss of Vangl1 limits the ability of endothelial cells to respond to shear forces in a coordinated fashion, resulting in irregular cell alignment along the flow direction and erroneous vessel sprouting. Together, these studies introduce core PCP signaling as a determinant of collective cell dynamics and organization of the vascular system.

cell biology↗

bioRxiv2021

DNA motif analysis of shear stress responsive endothelial enhancers reveals differential association of KLF and ETV/ETS binding sites with gained and lost enhancers

Endothelial cells (EC) lining blood vessels are exposed to mechanical forces, such as shear stress exerted by the flowing blood. These forces control many aspects of EC biology, including vascular tone, cell migration and proliferation in addition to cell size and shape. Despite a good understanding of the genes and signaling pathways responding to shear stress, our insights into the transcriptional regulation of these responses is much more limited. In particular, we do not know the different sets of regulatory elements (enhancers) that might control increases or decreases in gene expression. Here, we set out to study changes in the chromatin landscape of human umbilical vein endothelial cells (HUVEC) exposed to laminar shear stress. To do so, we performed ChIP-Seq for H3K27 acetylation, indicative of active enhancer elements and ATAC-Seq to mark regions of open chromatin in addition to RNA-Seq on HUVEC exposed to 6 hours of laminar shear stress. Our results show a correlation of gained and lost enhancers with up- and downregulated genes, respectively. DNA motif analysis revealed an over-representation of KLF transcription factor (TF) binding sites in gained enhancers, while lost enhancers contained more ETV/ETS motifs. We validated a subset of flow responsive enhancers using luciferase-based reporter constructs and CRISPR-Cas9 mediated genome editing. Lastly, we characterized shear stress responsive genes in ECs of zebrafish embryos using RNA-Seq. Together, our results reveal the presence of shear stress responsive DNA regulatory elements and lay the groundwork for the future exploration of these elements and the TFs binding to them in controlling EC biology.

genomics↗