Why the study?
Pathological high shear stress is generated in distal pulmonary arteries in congenital heart defects and progressive PAH, but whether it drives endothelial-mesenchymal transition was unknown.
Does replenishing ERG prevent high shear stress-induced endothelial-mesenchymal transition and pulmonary arterial hypertension in preclinical models?
Does replenishing ERG prevent high shear stress-induced endothelial-mesenchymal transition and pulmonary arterial hypertension in preclinical models?
Absolute Event Rate: 29.2% vs 37.2%
p-value: p=<0.01
Replenishing the transcription factor ERG in pulmonary artery endothelial cells may prevent high shear stress-induced endothelial-mesenchymal transition and progressive pulmonary arterial hypertension.
HSS-induced EndMT may drive PAH remodeling; leaves open whether shear or epigenetic targeting alters progression.
Pathological high shear stress (HSS, 100 dyn/cm 2 ) is generated in distal pulmonary arteries (PA) (100-500 μm) in congenital heart defects and in progressive PA hypertension (PAH) with inward remodeling and luminal narrowing. Human PA endothelial cells (PAEC) were subjected to HSS versus physiologic laminar shear stress (LSS, 15 dyn/cm 2 ). Endothelial-mesenchymal transition (EndMT), a feature of PAH not previously attributed to HSS, was observed. H3K27ac peaks containing motifs for an ETS-family transcription factor (ERG) were reduced, as was ERG-Krüppel-like factors (KLF)2/4 interaction and ERG expression. Reducing ERG by siRNA in PAEC during LSS caused EndMT; transfection of ERG in PAEC under HSS prevented EndMT. An aorto-caval shunt was preformed in mice to induce HSS and progressive PAH. Elevated PA pressure, EndMT and vascular remodeling were reduced by an adeno-associated vector that selectively replenished ERG in PAEC. Agents maintaining ERG in PAEC should overcome the adverse effect of HSS on progressive PAH.
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Shinohara et al. (2024) studied Pulmonary Arterial Hypertension. Adeno-associated virus encoding ERG (AAV-Erg) vs. AAV-luciferase (AAV-Con) was evaluated on Right ventricular systolic pressure (RVSP) (p=<0.01).
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