Biology subjects

Potente, M.

Publications and source records attributed to Potente, M..

6 recordsLinked to original sources

bioRxiv2026

Endothelial YAP/TAZ rewiring under cardiometabolic stress drives sex-divergent vascular remodeling in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is widely linked to endothelial dysfunction, yet the molecular pathways translating cardiometabolic stress into microvascular remodeling remain poorly defined. Here, we identify endothelial YAP/TAZ signaling as a mechanistic regulator of sex-divergent vascular responses in HFpEF. Plasma proteomics from the UK Biobank revealed elevated circulating YAP1 levels associated with heart failure and increased mortality, particularly in male patients, where YAP1 coincided with increased levels of the endothelial activation marker ESM1. In a hypertensive cardiorenal mouse model, endothelial YAP/TAZ deletion preserved cardiac function, whereas endothelial TAZ gain-of-function aggravated disease. Under cardiometabolic stress (TNF and high glucose), endothelial cells exhibited sex-specific rewiring of YAP/TAZ-dependent transcriptional programs. Male endothelial cells showed increased extracellular YAP1 release, angiogenic instability with impaired extracellular matrix remodeling, whereas female cells adopted an immune-primed, stress-adaptive phenotype. Mechanistically, cardiometabolic stress uncoupled canonical YAP-TEAD transcription and engaged alternative cofactors, including VGLL3 and VGLL4, thereby reshaping the endothelial secretome and propagating sex-divergent microvascular remodeling. These findings identify endothelial YAP/TAZ rewiring as a molecular switch that converts cardiometabolic stress into sex-divergent microvascular remodeling in HFpEF and connect this process to circulating YAP1 and ESM1 in patients.

cell biology↗

bioRxiv2024

YAP/TAZ signaling in allantois-derived cells is required for placental vascularization

Normal placental development and angiogenesis are crucial for fetal growth and maternal health during pregnancy. However, molecular regulation of placental angiogenesis has been difficult to study due to a lack of specific genetic tools that isolate the placenta from the embryo and yolk sac. To address this gap in knowledge we recently developed Hoxa13Cre mice in which Cre is expressed in allantois-derived cells, including placental endothelial and stromal cells. Mice lacking the transcriptional regulators Yes-associated protein (YAP) and PDZ-binding motif (TAZ) in allantois-derived cells exhibit embryonic lethality at midgestation with compromised placental vasculature. snRNA-seq analysis revealed transcriptional changes in placental stromal cells and endothelial cells. YAP/TAZ mutants exhibited significantly reduced placental stromal cells prior to the endothelial architectural change, highlighting the role of these cells in placental vascular growth. These results reveal a central role for YAP/TAZ signaling during placental vascular growth and implicate Hoxa13-derived placental stromal cells as a critical component of placental vascularization.

developmental biology↗

bioRxiv2024

Gut microbial metabolite imidazole propionate impairs endothelial cell function and promotes the development of atherosclerosis

BackgroundThe microbially generated amino acid-derived metabolite imidazole propionate (ImP) contributes to the pathogenesis of type 2 diabetes. However, the effect of ImP on endothelial cell physiology and its role in atherosclerotic coronary artery disease (CAD) is unknown. Using both human and animal model studies, we investigated the potential contributory role of ImP in the development of atherosclerosis. MethodsPlasma levels of ImP were measured in patients undergoing elective cardiac angiography (n = 831) by means of ultra high-performance liquid chromatography coupled to tandem mass spectrometry. Odds ratios (ORs) and corresponding 95% confidence intervals for CAD were calculated based on the ImP quartiles using both univariable and multivariable logistic regression models. Atheroprone apolipoprotein E-/- (Apoe-/-) mice fed a high-fat diet were additionally treated with ImP (800 {micro}g) or vehicle and aortic atherosclerotic lesion area was evaluated after 12 weeks. In a mouse model of carotid artery injury, the effect of ImP on vascular regeneration was examined. Using human aortic endothelial cells (HAECs) the effect of ImP on functional properties of endothelial cells were assessed. Next-generation sequencing, western blot analysis, siRNA-based gene knockdown and tamoxifen-inducible Cre-loxP experiments were performed to investigate ImP-mediated molecular mechanisms. ResultsPlasma ImP levels in subjects undergoing cardiac evaluation were associated with increased risk for prevalent CAD. In atheroprone Apoe-/- mice ImP increased atherosclerotic lesion size. We found that ImP dose-dependently impaired migratory and angiogenic properties of human endothelial cells, and promoted an increased inflammatory response. Long-term exposure to ImP impaired the repair potential of the endothelium after an arterial insult. Mechanistically, ImP attenuated insulin receptor signaling by suppressing PI3K/AKT pathway leading to the sustained activation of the forkhead box protein O1 (FOXO1) transcription factor. Genetic inactivation of endothelial FOXO1 signaling in ImP-treated mice enhanced the angiogenic activity and preserved the vascular repair capacity of endothelial cells after carotid injury. ConclusionsOur findings reveal a hitherto unknown role of the microbially produced histidine-derived metabolite ImP in endothelial dysfunction and atherosclerosis, suggesting that ImP metabolism is a potential therapeutic target in atherosclerotic cardiovascular disease.

systems biology↗

bioRxiv2023

Stabilisation of β-Catenin-WNT signalling by USP10 in APC-truncated colorectal cancer drives cancer stemness and enables super-competitor signalling

The contribution of deubiquitylating enzymes to {beta}-Catenin stabilisation in intestinal stem cells and colorectal cancer (CRC) is poorly understood. Here, we report the deubiquitylase USP10 as an APC-truncation- specific enhancer of {beta}-Catenin stability, potentiating WNT signalling in CRC and cancer stem cells. Mechanistically, interaction studies in various CRC cell lines and in vitro binding studies, together with computational modelling, revealed that USP10 binding to {beta}-Catenin is mediated via the unstructured N-terminus of USP10 and requires the absence of full-length APC. Notably, loss of USP10 in CRISPR engineered intestinal organoids reduces tumorigenic properties of CRC and blocks the super competitor-signalling of APC-mutated CRC. Furthermore, reduction of USP10 induces the expression of differentiation genes, and opposes the APC-truncated phenotype in an intestinal hyperplasia model of D.melanogaster. Taken together, our findings reveal USP10s role in intestinal tumourigenesis by stabilising {beta}-Catenin, leading to aberrant WNT signalling, enhancing cancer cell stemness and implicate the DUB USP10 as a cancer specific therapeutic vulnerability in Apc truncated CRC.

cancer biology↗

bioRxiv2022

Rnf20 shapes the endothelial control of heart morphogenesis and function

During embryogenesis, distinct cardiac cell types form, which shape the structural and functional properties of the heart. How their activity is coordinated is largely unknown. Here we show that Rnf20 is a multifaceted regulator of cardiac morphogenesis and function. On the one hand, Rnf20 controls extracellular matrix dynamics and endothelial-cardiomyocyte crosstalk essential for second heart field development. On the other hand, it safeguards endothelial cell identity and function by maintaining physiological angiocrine signaling and preventing endothelial-to-mesenchymal transition. Endothelial-specific deletion of Rnf20 led to ventricular septal defects, myocardial thinning and cardiac dysfunction as a result of aberrant signaling and excessive extracellular matrix deposition that induced precocious cardiomyocyte binucleation and irregular contractility. Furthermore, we uncovered upstream factors (e.g. Sox9) and multiple angiocrine and extracellular matrix molecules that alter cardiomyocyte functionality upon endothelial Rnf20 loss. In summary, our work identifies a novel, endothelial-specific role of Rnf20 in regulating cardiac morphogenesis and function.

developmental 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↗