FOXO1 unlocks SMAD function to drive mechano-induced endothelial-to-mesenchymal transition

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Abstract
Endothelial-to-mesenchymal transition (EndMT) contributes to vascular remodeling and endothelial dysfunction in diseases such as atherosclerosis and pulmonary arterial hypertension. This process describes a gradual shift in which endothelial cells (ECs) lose expression of classical EC markers and acquire mesenchymal-like gene expression patterns and phenotypic traits. Although SMAD transcription factors are key regulators of EndMT, driven by mechanical cues from disturbed flow that activate BMP or TGFβ signaling, their weak DNA-binding affinity invoked the need for additional transcriptional co-factors to specify gene targets under pathophysiological flow conditions. Here, we identified FOXO1 as a transcriptional co-factor that cooperates with SMADs to regulate mesenchymal gene expression in ECs exposed to irregular flow. FOXO1 and SMADs co-occupy genomic loci and form transcriptional complexes. Although SMAD DNA binding is FOXO1-independent, FOXO1 activity is required for full induction of SMAD target genes. Notably, FOXO1 DNA-binding activity is essential for robust activation of EndMT-associated genes, as both pharmacological inhibition and siRNA-mediated depletion of FOXO1 attenuate SMAD target gene expression. Functionally, combined targeting of FOXO1 and SMAD signaling rescues EndMT-associated endothelial dysfunction in carotid arteries of mice. Our results describe FOXO1 as key integrator of SMAD-mediated EndMT signaling, linking it to pathogenic SMAD activation in disease contexts.

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