The role of SOX17 in the shear stress response of the arterial endothelium

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Background: Rare and common genetic variants in SOX17 worsen PAH and accelerate disease progression. Although SOX17 is known as an embryonic transcription factor for arterial differentiation and angiogenesis, its function in the adult vasculature is unclear. We hypothesized that SOX17 drives resilience of the arterial endothelium under shear stress, and that impaired SOX17 expression predisposes for pulmonary endothelial injury. Results: Exposure of healthy pulmonary artery endothelial cells (PAECs) to physiological shear stress of 15 dyn/cm2 resulted in a 2-3 fold increase in SOX17 RNA and protein levels. Short hairpin RNA (shRNA)-mediated SOX17 depletion significantly reduced cell elongation under flow, increased the number and size of intercellular gaps, and impaired barrier integrity as assessed with ECIS. Additionally, SOX17-depletion reduced VE-cadherin levels in 2D cells, as well as in a 3D vessel-on-a-chip model. Regenerative capacity was also disturbed, with a significant reduction in Ki67-positive cells, decreased RNA expression of cell cycle markers CyclinD1/E1, and impaired wound healing capacity. Mechanistically, we identified the endothelial-secreted protein Semaphorin 3G (SEMA3G) downstream of SOX17 in knockdown and overexpression conditions. Addition of SEMA3G protein to SOX17-depleted PAECs rescues the phenotype and restored the expression of VE-cadherin at the adherens junctions. Conclusion: The presence of SOX17 is crucial for the maintenance of cell junctions and barrier integrity under fluid shear stress. Impaired SOX17 expression sensitizes the arterial endothelium to damage, and may contribute to the pulmonary vascular remodeling observed in PAH.

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