Biology subjects

Vion, A.-C.

Publications and source records attributed to Vion, A.-C..

6 recordsLinked to original sources

bioRxiv2025

NET1/ARHGEF8 is a mechanosensitive Guanine Exchange Factor controlling vascular smooth muscle cells' contractility

Cyclic stretch, generated by pulsatile blood pressure, has been identified as a pivotal regulator of vascular smooth muscle cell (VSMC) behavior and arterial wall homeostasis. Research has demonstrated that RhoA activation is a fundamental component of VSMC responses to mechanical stress through its action on cytoskeletal remodeling. However, the upstream mechanosensitive regulators of RhoA activation remain insufficiently defined. In this study, we identify the guanine nucleotide exchange factor (RhoGEF) NET1/ARHGEF8 as a stretch-responsive protein. NET1 appears to be highly expressed in arteries and VSMCs. Under physiological levels of cyclic stretch, NET1 localizes to the cytosol and interacts with RhoA. In contractile cells, loss of NET1 blunted stretch-induced MYPT1 phosphorylation and impaired cell adhesion and spreading, without exerting any effect on cell proliferation. As we demonstrated, NET1s contribution to the stretch-induced response of VSMC was due to its localization in the cytosol. The expression of a cytosolic NET1 mutant promoted contractile gene expression and increased cell contractile capacity. Collectively, these findings identify NET1 as a stretch-sensitive RhoGEF in VSMCs that contributes to their adhesion and contractile behavior.

cell biology↗

bioRxiv2025

ANGPTL6 variant induces cerebral vascular dysfunction and predisposes to intracranial aneurysm in mice

BackgroundIntracranial aneurysm (IA) is a common cerebrovascular abnormality characterized by localized dilation and wall thinning in intracranial arteries, that frequently leads to fatal sub-arachnoid hemorrhage. Pathophysiological mechanisms responsible for AI remains largely unknown, but increasing evidence suggest that genetic susceptibility plays a predominant role. We recently identified a rare nonsense variant in ANGPTL6 gene that prevented angiopoietin-like 6 (ANGPTL6) secretion and predisposed to IA. The aim of this study is now to understand why the ANGPTL6 variant predisposes to IA. MethodsAngptl6-knock in mice were generated by homologous recombination. Cerebral arteries of the circle of Willis have been analyzed under basal and hemodynamic overload conditions. Functional properties of cerebral arteries have been analyzed by pressure arteriography. Effect of recombinant ANGPTL6 have been assessed on vascular smooth muscle cells and ANGPTL6 partners have been analyzed by surface plasmon resonance. ResultsAngptl6-knock in mice display endothelial dysfunction expressed by reduced NO production in response to flow in cerebral arteries. They present exaggerated dilatation of cerebral arteries under hypertensive stress, and aggravated wall damage and aneurysmal remodeling of the intima and media at arterial bifurcations of the circle of Willis under hemodynamic overload. Matrix bound ANGPTL6 decreased VSMC migration and increased adhesion and FAK signaling activation, without affecting VSMC phenotype. Surface plasmon resonance analyses identified v{beta}5 integrin as a new ANPTL6 receptor. ConclusionsAngptl6-knock in mice mimicked the main features of IA in humans. ANGPTL6 appears to be an extracellular matrix component regulating vascular cell function, which may be involved in mechanosensing and generating adapted vascular cell responses to hemodynamic stress. Non-secreted ANGPTL6 variants would result in the loss of this function, thus favoring IA under conditions of hemodynamic overload.

physiology↗

bioRxiv2022

ARHGEF18 participates in Endothelial Cell Mechano-sensitivity in Response to Flow

The shear stress resulting from blood flow is a major regulator of endothelial cell (EC) biology and morphology. Rho protein-mediated cytoskeleton remodeling is an early and essential step of EC responses to flow. However, how Rho protein signaling is controlled by shear stress remains unclear. Here we demonstrate that phosphorylation, activity and expression of the Rho nucleotide exchange factor (RhoGEF) ARHGEF18 in ECs are modulated by the magnitude of shear stress. ARHGEF18 interacts with tight junctions, participates in ECs elongation and alignment and allows the maintenance of the endothelial barrier under physiological flow conditions. ARHGEF18 also promotes EC adhesion and migration by controlling focal adhesion formation. In vivo, ARHGEF18 is involved in flow response of ECs and in the control of vascular permeability in mice. Together, our results identified ARHGEF18 as the first flow-sensitive RhoGEF in ECs, whose activity is essential for the maintenance of intercellular junctions and the control of vascular permeability in vivo.

cell biology↗

bioRxiv2019

Endothelial PKA targets ATG16L1 to regulate angiogenesis by limiting autophagy

The cAMP-dependent protein kinase A (PKA) regulates a plethora of cellular functions in health and disease. During angiogenesis, PKA activity in endothelial cells controls the transition from sprouting to vessel maturation and limits tip cell formation independently of Notch signaling. The molecular PKA targets mediating these effects remain unknown. We report a chemical genetics screen identifying endothelial-specific substrates of PKA in human umbilical vein endothelial cells (HUVEC). We identified ATG16L1, a regulator of autophagy, as novel target of PKA. Biochemical validation, mass spectrometry and peptide spot arrays revealed that PKA phosphorylates ATG16L1 at Ser268 and ATG16L1{beta} at Ser269. The phosphorylations drive degradation of ATG16L1 protein. Knocking down PKA or inhibiting its activity increased ATG16L1 protein levels and endothelial autophagy. In vivo genetics and pharmacological experiments demonstrated that autophagy inhibition partially rescues vascular hypersprouting caused by PKA deficiency. We propose that endothelial PKA activity restricts active sprouting by reducing endothelial autophagy through phosphorylation of ATG16L1.

biochemistry↗

bioRxiv2018

Arterio-Venous Remodeling in the Zebrafish Trunk Is Controlled by Genetic Programming and Flow-Mediated Fine-Tuning

How developing vascular networks acquire the right balance of arteries, veins and lymphatics to efficiently supply and drain tissues is poorly understood [1, 2]. In zebrafish embryos, the robust and regular 50:50 global balance of intersegmental veins and arteries that form along the trunk [3], prompts the intriguing question how the organism keeps \"count\". Previous studies suggest that the ultimate fate of an intersegmental vessel (ISV) is determined by the identity of the approaching secondary sprout emerging from the posterior cardinal vein (PCV) [1, 4-7]. Here, using high time-resolution imaging, advanced cell tracking and computational analysis, we show that the formation of a balanced trunk vasculature involves an early heterogeneity in endothelial cell (EC) behavior in the seemingly identical primary ISVs and an adaptive flow-mediated mechanism that fine-tunes the balance of arteries and veins along the trunk. Detailed examination of the trunk vasculature dynamics throughout development reveals the frequent formation of three-way vascular connections between primary ISVs, the dorsal aorta (DA) and the PCV. Differential resolution of these connections into arteries or veins is mediated by polarized cell movement of the ECs within the ISV. Quantitative analysis of the cellular organization, polarity and directional movement of ECs in primary ISVs identifies an early differential behavior between future arteries and veins that is largely specified in the ECs of the individual ISVs, is dependent on Dll4/Notch, and occurs even in the absence of secondary sprouting. Notch signaling is involved in a local patterning mechanism normally favoring the formation of alternating arteries and veins. The global artery-vein balance is however maintained through a flow-dependent mechanism that can overwrite the local patterning. We propose that this dual mechanism driving arterio-venous identity during developmental angiogenesis in the zebrafish trunk provides the adaptability required to establish a balanced network of arteries, veins and lymphatic vessels.

cell biology↗

bioRxiv2017

YAP and TAZ regulate adherens junction dynamics and endothelial cell distribution during vascular development

Formation of a hierarchically organized blood vessel network by sprouting angiogenesis is critical for tissue growth, homeostasis and regeneration. How in this process endothelial cells arise in adequate numbers and arrange suitably to shape a functional vascular network is poorly understood. Here we show that YAP and TAZ promote stretch-induced proliferation and rearrangements of endothelial cells whilst preventing bleeding in developing vessels. Mechanistically, YAP and TAZ increase VE-cadherin turnover at junctions and suppress endothelial Notch and BMP signaling, two key pathways that limit sprouting and endothelial dynamics. Consequently, the loss of YAP and TAZ leads to stunted sprouting with local aggregation as well as scarcity of endothelial cells, branching irregularities and junction defects. Forced nuclear activity of TAZ instead drives hypersprouting and vascular hyperplasia. We propose a new model in which YAP and TAZ integrate mechanical signals with Notch and BMP signaling to balance endothelial cell distribution in angiogenic vessels.

developmental biology↗