High Shear Stress Reduces ERG Causing Endothelial-Mesenchymal Transition and Pulmonary Arterial Hypertension

• DOI: 10.1161/atvbaha.124.321092
• Publication Date: 2024-12-26T10:00:27Z
• Authors: Tsutomu Shinohara; Jan-Renier Moonen; Yoon Hong Chun; Yannick C. Lee-Yow; Kenichi Okamura; Jason M. Szafron; Jordan Kaplan; Aiqin Cao; Lingli Wang; Divya Guntur; Shalina Taylor; Sarasa Isobe; Melody Dong; Weiguang Yang; Katherine Guo; Benjamin D. Franco; Cholawat Pacharinsak; Laura J. Pisani; Shinji Saitoh; Yoshihide Mitani; Alison L. Marsden; Jesse M. Engreitz; Jakob Körbelin; Marlene Rabinovitch
• Keywords: KLF2; Erg

Computational modeling indicated that pathological high shear stress (HSS; 100 dyn/cm2) is generated in pulmonary arteries (PAs; 100-500 µm) congenital heart defects causing PA hypertension (PAH) and idiopathic PAH with occlusive vascular remodeling. Endothelial-to-mesenchymal transition (EndMT) a feature of PAH. We hypothesize HSS induces EndMT, contributing to the initiation progression used Ibidi perfusion system determine whether applied human endothelial cells (ECs) EndMT when compared physiological laminar (15 dyn/cm2). The mechanism was investigated targeted prevent mouse induced by an aortocaval shunt. not previously attributed HSS, observed. did alter induction transcription KLF (Krüppel-like factor) 2/4, but ERG (ETS-family reduced, as were histone H3 lysine 27 acetylation enhancer-promoter peaks containing motifs. Consequently, there reduced interaction between KLF2/4, important tethering chromatin remodeling complex DNA. In ECs under stress, reducing siRNA caused associated decreased BMPR2 (bone morphogenetic protein receptor 2), CDH5 (cadherin 5), PECAM1 (platelet EC adhesion molecule 1) increased SNAI1/2 (Snail/Slug) ACTA2 (smooth muscle α2 actin). transfection prevented EndMT. then mice shunt, progressive over 8 weeks. An adeno-associated viral vector (AAV2-ESGHGYF) replenish selectively ECs. Elevated pressure, (muscularization peripheral arteries) shunt markedly delivery. Pathological lung ERG, resulting Agents upregulate could reverse HSS-mediated from flow or narrowed PAs.