Tsutomo Shinohara, Jan-Ranier 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
Lucile Packard Children’s Hospital and Stanford University School of Medicine. Incheon St. Mary’s Hospital and Catholic University of Korea College of Medicine. Medical University of Graz. Nagoya City University Graduate School of Medical Sciences. Mie University Graduate School of Medicine. University Medical Center Hamburg-Eppendorf.
United States, Republic of Korea, Austria, Japan and Germany
Arteriosclerosis, Thrombosis and Vascular Biology
Arterioscler Thromb Vasc Biol 2024;
DOI: 10.1161/ATVBAHA.124.321092
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 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 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.
Category
Class I. Pulmonary Hypertension Associated with Congenital Cardiovascular Disease
Mechanical and Computer Models of Pulmonary Vascular Disease and Therapy
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: No