Abstract Body: Background: Endothelial dysfunction and pathological vascular remodeling are central to cardiovascular diseases including pulmonary hypertension (PH), atherosclerosis, fibrotic vascular disease, and systemic endothelial dysfunction. Endothelial-to-mesenchymal transition (EndMT) links endothelial plasticity to excessive proliferation, barrier disruption, inflammation, and neointimal lesion formation across vascular beds. Hypoxia induces endothelial plasticity, however, the molecular mechanisms coordinating this process in lung vascular endothelial cells (EC) remain incompletely understood. We hypothesized that hypoxia-activated STAT3 signaling promotes endothelial dysfunction through microRNA-dependent regulation of EndMT programs.
Methods: Human lung vascular EC were exposed to hypoxia (3% O2) or TGF-β1 to induce EndMT, while EC-specific STAT3 knockout mice were subjected to chronic hypoxia to model PH. EndMT markers, STAT3 signaling, micri-RNA-153, and endothelial barrier function were assessed using molecular, imaging, and permeability assays. Human lung tissues from patients with PH were analyzed for clinical validation.
Results: Hypoxia induced STAT3 activation, downregulated microRNA-153, and increased expression of the EndMT transcription factors SNAI1 and SNAI2, resulting in loss of endothelial markers, acquisition of mesenchymal markers, enhanced EC survival, and increased monolayer permeability. Genetic or siRNA-mediated STAT3 inhibition restored endothelial junctional integrity and prevented hypoxia-induced EndMT in vitro. EC-specific STAT3 deletion significantly attenuated vascular leakage, EndMT, pulmonary vascular remodeling, and right ventricular hypertrophy in hypoxic mice. Consistently, human PH lung tissues and cells demonstrated the lower microRNA-153 level while the increased phosphorylated STAT3 and SNAI1/2 expression compared with controls.
Conclusions: These findings identify a STAT3–microRNA-153–SNAI signaling axis as a central regulator of endothelial plasticity, barrier dysfunction, and pathological vascular remodeling. By linking EndMT to systemic endothelial dysfunction, this work provides mechanistic insight broadly relevant to atherosclerosis, fibrotic vascular remodeling, and cardiopulmonary vascular disease, and highlights STAT3–microRNA-153 signaling as a potential therapeutic target.