Beta arrestin 1 is a key regulator of pulmonary vascular tone

• 成果类型: Article
• 署名作者: Lebender, Leonard F.; Seidinger, Alexander; Matthey, Michaela; Dyck, Birte; Schlamm, Christian; Kaddoura, Abdullah; Hausherr, Maximilian; Eggers, Britta; Marcus, Katrin; Kostenis, Evi; Gieselmann, Volkmar; Adamzik, Michael; Klinke, Anna; Koos, Bjorn; Fleischmann, Bernd K.; Wenzel, Daniela
• 署名单位: University of Bonn; Ruhr University Bochum; Ruhr University Bochum; Ruhr University Bochum; Ruhr University Bochum; University of Bonn; University of Bonn
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2512602123
• 发表日期: 2026-02-17
• 页码: e2512602123
• 关键词: beta arrestin; soluble guanylyl cyclase; pulmonary hypertension; SOLUBLE GUANYLATE-CYCLASE; RECEPTOR KINASE 2; nitric-oxide; activation; roles; mice; HEAT-SHOCK-PROTEIN-90; hypertension; responses

摘要

Pulmonary arterial hypertension (PAH) is a serious disorder, in which increased vascular tone is one of the critical hallmarks. Since beta arrestins (bArrs) have been shown to regulate smooth muscle tone in the airways, we investigated the function of bArr1 in the pulmonary vasculature. Here, we report that bArr1 is essential for maintaining normal pulmonary arterial tone. Specifically, pulmonary arteries from bArr1-/- mice exhibited reduced NO-dependent vasorelaxation due to impaired soluble guanylyl cyclase (sGC) activity, which was restored by the heme-independent sGC activator BAY58-2667. We identified bArr1 as a binding partner of sGC and the sGC heme reductase cytochrome b5 reductase (Cyb5r3), indicating that bArr1 is vital for sensitizing sGC to NO. Finally, mice with either ubiquitous or smooth muscle-specific bArr1 deficiency developed pulmonary hypertension (PH). These findings highlight the important role of bArr1 in regulating pulmonary vascular tone and propose it as a potential therapeutic target for the treatment of PH.