講演情報
[III-TLR-4]Mechanobiological Regulation of Pulmonary Arterial Hypertension: High Shear Stress-Driven ERG Loss and Endothelial Dysfunction
○Tsutomu Shinohara1, Jan-Renier Moonen2, Marlene Rabinovitch2 (1.Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan, 2.Stanford University School of Medicine)
キーワード：
Shear stress、pulmonary arterial hypertension、endothelial-to-mesenchymal transition
Background: Shear stress is a biomechanical force acting parallel to blood flow on vascular endothelial cells. Computational fluid dynamics predict that pathological high shear stress (HSS, 100 dyn/cm2) develops in distal pulmonary arteries in congenital heart defects with increased pulmonary blood flow and idiopathic pulmonary arterial hypertension (PAH) with occlusive remodeling. However, the transcriptional consequences of HSS in pulmonary arterial endothelial cells (PAECs) remain incompletely understood. Methods: We exposed human PAECs to HSS (100 dyn/cm2) or physiological laminar shear stress (LSS, 15 dyn/cm2) using a flow perfusion system and analyzed transcriptional regulation by CUT&RUN. Results: HSS induced endothelial-to-mesenchymal transition (EndMT). HSS markedly reduced expression of the ETS-family transcription factor ERG. Under LSS, ERG knockdown by siRNA induced EndMT. Conversely, ERG overexpression under HSS prevented EndMT. To validate these findings in vivo, HSS was induced in mice using an aortocaval shunt model, resulting in progressive PAH over eight weeks. Endothelial-selective ERG replenishment using an adeno-associated viral vector significantly reduced pulmonary arterial pressure, EndMT, and peripheral arterial muscularization. Conclusions: These results demonstrate that pathological HSS directly alters endothelial transcriptional regulation via ERG suppression, promoting EndMT and progressive PAH. Targeting ERG represents a novel mechanobiology-based therapeutic strategy for PAH associated with high flow or vascular narrowing.