TY - JOUR AU - Fang, Shi AU - Wu, Jing AU - Reho, John J. AU - Lu, Ko-Ting AU - Brozoski, Daniel T. AU - Kumar, Gaurav AU - Werthman, Alec M. AU - Silva, Sebastiao Donato, Jr. AU - Muskus Veitia, Patricia C. AU - Wackman, Kelsey K. AU - Mathison, Angela J. AU - Teng, Bi Qing AU - Lin, Chien-Wei AU - Quelle, Frederick W. AU - Sigmund, Curt D. T1 - RhoBTB1 reverses established arterial stiffness in angiotensin II–induced hypertension by promoting actin depolymerization PY - 2022/05/09/ AB - Arterial stiffness predicts cardiovascular disease and all-cause mortality, but its treatment remains challenging. Mice treated with angiotensin II (Ang II) develop hypertension, arterial stiffness, vascular dysfunction, and a downregulation of Rho-related BTB domain–containing protein 1 (RhoBTB1) in the vasculature. RhoBTB1 is associated with blood pressure regulation, but its function is poorly understood. We tested the hypothesis that restoring RhoBTB1 can attenuate arterial stiffness, hypertension, and vascular dysfunction in Ang II–treated mice. Genetic complementation of RhoBTB1 in the vasculature was achieved using mice expressing a tamoxifen-inducible, smooth muscle–specific RhoBTB1 transgene. RhoBTB1 restoration efficiently and rapidly alleviated arterial stiffness but not hypertension or vascular dysfunction. Mechanistic studies revealed that RhoBTB1 had no substantial effect on several classical arterial stiffness contributors, such as collagen deposition, elastin content, and vascular smooth muscle remodeling. Instead, Ang II increased actin polymerization in the aorta, which was reversed by RhoBTB1. Changes in the levels of 2 regulators of actin polymerization, cofilin and vasodilator-stimulated phosphoprotein, in response to RhoBTB1 were consistent with an actin depolymerization mechanism. Our study reveals an important function of RhoBTB1, demonstrates its vital role in antagonizing established arterial stiffness, and further supports a functional and mechanistic separation among hypertension, vascular dysfunction, and arterial stiffness. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.158043 VL - 7 IS - 9 UR - https://doi.org/10.1172/jci.insight.158043 PB - The American Society for Clinical Investigation ER -