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• W4283814219 abstract "Abstract Background Vascular networks form, remodel and mature under the influence of both fluid shear stress (FSS) and soluble factors. For example, FSS synergizes with Bone Morphogenic Protein 9 (BMP9) and BMP10 to promote and maintain vascular stability. Mutation of the BMP receptors ALK1, Endoglin or the downstream effector SMAD4 leads to Hereditary Hemorrhagic Telangiectasia (HHT), characterized by fragile and leaky arterial-venous malformations (AVMs). But how endothelial cells (EC) integrate FSS and BMP signals in normal vascular development and homeostasis, and how mutations give rise to malformations is not well understood. Results Here we show that loss of Smad4 in murine ECs increases cells’ sensitivity to flow and the resulting AVMs are characterized by excessive elongation and polarity against the flow. Smad4 deletion also blocks the anti-proliferative response to high FSS, leading to loss of arterial identity. Our data show that loss of cell cycle arrest leads to loss of arterial identity, which is essential in AVM formation upon Smad4 depletion in ECs. Excessive flow-induced activation of KLF4-PI3K/AKT due to Cyclin dependent Kinase (CDK) activation mediates the aberrant morphological responses to flow triggering AVM formation. Conclusions Our results show that loss of polarization against the flow is not required for AVM formation upon EC Smad4 depletion. Instead, increased EC proliferation-mediated loss of arterial identity due to flow-induced PI3K/Akt/Cdks hyperactivation and Klf4 over-expression are the main events associated with AVM formation." @default.
• W4283814219 created "2022-07-06" @default.
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• W4283814219 date "2022-07-04" @default.
• W4283814219 modified "2023-10-08" @default.
• W4283814219 title "Excessive fluid shear stress-mediated Klf4 leads to arteriovenous pathogenesis" @default.
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• W4283814219 doi "https://doi.org/10.1101/2022.07.04.498236" @default.
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