Endothelial mechanosensitive transcription factor NR4A1 induced by Piezo1 modulates thrombosis via PTGS2

Endothelial dysfunction-induced platelet activation contributes to thrombosis in major cardiovascular diseases. Endothelial cells sense hemodynamic shear stress via the mechanosensitive ion channel Piezo1, which determines their physiological functions. However, the downstream transcriptional pathways of Piezo1 linking mechanical force to endothelial function remain incompletely defined. Here, nuclear receptor subfamily 4 group A member 1 (NR4A1) is identified as an endothelial mechanosensitive transcription factor induced by Piezo1 that modulates platelet activation and thrombosis. Mechanistically, shear stress is shown to activate Piezo1, resulting in calcium influx and the subsequent activation of protein kinase C δ (PKCδ), which activates extracellular signal-regulated kinase (ERK) to induce NR4A1 transcription. NR4A1 then upregulates prostaglandin-endoperoxide synthase 2 (PTGS2) expression, leading to the increased production of prostacyclin and inhibition of platelet activation and thrombosis. In vivo, mice with endothelial cell-specific deletion of Nr4a1 exhibit greater thrombus weights and faster occlusion. These data establish the Piezo1/Ca2+/PKCδ/ERK/NR4A1/PTGS2 signaling cascade as a critical endothelial mechanotransduction pathway that senses physiological shear force to transcriptionally promote an antithrombotic state.