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. 2025 Feb;45(2):218-237.
doi: 10.1161/ATVBAHA.124.321092. Epub 2024 Dec 26.

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

Tsutomu Shinohara #  1   2   3   4   5 , Jan-Renier Moonen #  1   2   3   4 , Yoon Hong Chun  1   2   3   6 , Yannick C Lee-Yow  4   7 , Kenichi Okamura  2   8 , Jason M Szafron  1   2   3   9 , Jordan Kaplan  1   2   3   4 , Aiqin Cao  1   2   3   4 , Lingli Wang  1   2   3   4 , Divya Guntur  1   10 , Shalina Taylor  1   3   4 , Sarasa Isobe  1   2   3   4   11 , Melody Dong  1   2   3   12 , Weiguang Yang  1 , Katherine Guo  4   7 , Benjamin D Franco  13 , Cholawat Pacharinsak  13 , Laura J Pisani  14 , Shinji Saitoh  15 , Yoshihide Mitani  16 , Alison L Marsden  1   2   3   12 , Jesse M Engreitz  2   4   7 , Jakob Körbelin  17 , Marlene Rabinovitch  1   2   3   4
Affiliations

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

Tsutomu Shinohara et al. Arterioscler Thromb Vasc Biol. 2025 Feb.

Abstract

Background: Computational modeling indicated that pathological high shear stress (HSS; 100 dyn/cm2) is generated in pulmonary arteries (PAs; 100-500 µm) in congenital heart defects causing PA hypertension (PAH) and in idiopathic PAH with occlusive vascular remodeling. Endothelial-to-mesenchymal transition (EndMT) is a feature of PAH. We hypothesize that HSS induces EndMT, contributing to the initiation and progression of PAH.

Methods: We used the Ibidi perfusion system to determine whether HSS applied to human PA endothelial cells (ECs) induces EndMT when compared with physiological laminar shear stress (15 dyn/cm2). The mechanism was investigated and targeted to prevent PAH in a mouse with HSS induced by an aortocaval shunt.

Results: EndMT, a feature of PAH not previously attributed to HSS, was observed. HSS did not alter the induction of transcription factors KLF (Krüppel-like factor) 2/4, but an ERG (ETS-family transcription factor) was reduced, as were histone H3 lysine 27 acetylation enhancer-promoter peaks containing ERG motifs. Consequently, there was reduced interaction between ERG and KLF2/4, a feature important in tethering KLF and the chromatin remodeling complex to DNA. In PA ECs under laminar shear stress, reducing ERG by siRNA caused EndMT associated with decreased BMPR2 (bone morphogenetic protein receptor 2), CDH5 (cadherin 5), and PECAM1 (platelet and EC adhesion molecule 1) and increased SNAI1/2 (Snail/Slug) and ACTA2 (smooth muscle α2 actin). In PA ECs under HSS, transfection of ERG prevented EndMT. HSS was then induced in mice by an aortocaval shunt, causing progressive PAH over 8 weeks. An adeno-associated viral vector (AAV2-ESGHGYF) was used to replenish ERG selectively in PA ECs. Elevated PA pressure, EndMT, and vascular remodeling (muscularization of peripheral arteries) in the aortocaval shunt mice were markedly reduced by ERG delivery.

Conclusions: Pathological HSS reduced lung EC ERG, resulting in EndMT and PAH. Agents that upregulate ERG could reverse HSS-mediated PAH and occlusive vascular remodeling resulting from high flow or narrowed PAs.

Keywords: ERG; aorto-caval shunt mice; endothelial cells; endothelial-mesenchymal transition; pulmonary arterial hypertension; shear stress.

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Conflict of interest statement

J. Körbelin is an inventor on, and received royalties for, a patent on the capsid-modified AAV-ESGHGYF vector, assigned to Boehringer Ingelheim International GmbH (“Peptides Having Specificity for the Lungs”; US20230181683A1). J.M. Engreitz is a consultant and equity holder in Martingale Labs, Inc, and has received materials from 10× Genomics unrelated to this study. The other authors report no conflicts.

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