Rho‐related BTB domain‐containing protein 1 (RhoBTB1) is associated with blood pressure in GWAS studies, but its function is not well‐understood. The level of RhoBTB1 mRNA was decreased in mice treated with angiotensin II (Ang‐II) concomitant with hypertension, arterial stiffness, and impaired vasodilation. Here, we tested the hypothesis that restoration of RhoBTB1 would reverse hypertension, arterial stiffness, and improve vasodilation response caused by Ang‐II infusion. Genetic complementation of RhoBTB1 in the vasculature was achieved by expressing a smooth muscle‐specific, tamoxifen‐inducible RhoBTB1 transgene (S‐RhoBTB1 mice). Mice expressing smooth muscle‐specific, tamoxifen‐inducible Cre‐recombinase without RhoBTB1 (ISM‐Cre mice) were used as genotype control. ISM‐Cre and S‐RhoBTB1 mice received 6 weeks of Ang‐II infusion, but their transgene was not activated until two weeks after the initiation of Ang‐II treatment. Meanwhile, vehicle‐treated ISM‐Cre and S‐RhoBTB1 mice were used as control. Blood pressure was continuously recorded by radiotelemetry during the entire protocol. Pulse wave velocity (PWV) and aortic compliance assay were used to evaluate arterial stiffness both during and at the end of the protocol. Vasodilation was measured in isolated carotid and mesenteric arteries using wire myography. In vehicle‐treated mice, aortic RhoBTB1 expression was increased in S‐RhoBTB1 mice compared to ISM‐Cre mice. Ang‐II significantly decreased the level of RhoBTB1 in the aorta of ISM‐Cre mice whereas S‐RhoBTB1 mice normalized this effect. At baseline, overexpressing RhoBTB1 in the vasculature had no significant effect on any phenotype. Before transgene activation, Ang‐II increased blood pressure, arterial stiffness, and impaired vasodilation in response to acetylcholine and sodium nitroprusside in both ISM‐Cre and S‐RhoBTB1 mice. Remarkably, in Ang‐II‐treated mice, RhoBTB1 restoration restored arterial stiffness nearly back to baseline without rescuing either hypertension or vasodilation. Since arterial stiffness is often observed to go hand‐in‐hand with hypertension, the current phenotype is particularly interesting as it provides novel insight into the cause‐effect relationship between arterial stiffness and hypertension. Next, we utilized RNA‐seq and biochemical assays to investigate the mechanism by which RhoBTB1 reversed arterial stiffness. Classical contributors of arterial stiffness, for instance, collagen, elastin, and vascular smooth muscle remodeling, were not altered by RhoBTB1 restoration. However, actin polymerization was elevated by Ang‐II and normalized upon RhoBTB1 restoration, as evident by both immunoblotting and fluorescent labeling. In conclusion, we identified a novel function of RhoBTB1 and showed its importance in protecting from and reversing arterial stiffness.
Low-renin hypertension is a common subset of hypertensive patients, which is associated with salt sensitivity. Deoxycorticosterone (DOCA)-salt hypertension, a prototypical model of low-renin hypertension, requires activation of the angiotensin type-1 receptor (AT1R) in specific brain areas. G protein-mediated signaling of the AT1R within the brain is known to induce dipsogenic and pressor responses to Ang II stimulation. Non-canonical or b-arrestin-mediated signaling is thought to counterbalance the maladaptive G-protein (Gαq) signaling during disease. Recently, we found that global deletion of β-arrestin2 (ARRB2) exhibited an exacerbated increase in blood pressure (BP) in response to DOCA-salt compared to WT suggesting a protective role for ARRB2. However, the role of the non-canonical AT1R/β-arrestin pathway within the brain is understudied. Consequently, we hypothesized that b-Arrestin activation within the brain contributes to BP regulation. Global male and female β-arrestin1 ( Arrb1)- and β-arrestin2 ( Arrb2)-KO mice were employed to evaluate acute BP response upon treatment with intracerebroventricular (ICV) infusion of AngII (1ug). Age- and sex-matched C57BL/6 mice served as controls. Mice were simultaneously instrumented with radiotelemeters and ICV-cannula, BP was continuously recorded before and after AngII infusion in awake animals. At baseline, Arrb2-KO mice showed a slight increase in BP WT (WT=134.0±10.7 vs Arrb2-KO=143.7±17.2 mmHg; n=14 and 19, respectively). Further, Arrb2-KO mice exhibited significantly higher BP in response to AngII (WT=143.7±17.2 vs Arrb2-KO=176.9±24.2 mmHg; n=14 and 19, respectively p<0.05). These findings suggest that loss of ARRB2 exacerbates the pressor response to AngII within the brain. Additionally, we evaluated BP upon activation β-arrestin using TRV120027 (TRV27), a β-arrestin biased agonist specific for the AT1R. We used the BPH2/J genetic mouse model of low renin hypertension. Mice were subjected to continuous infusion of TRV27 (6ug/h), and telemetric BP was continuously recorded. BPN/2J mice were used as the normotensive controls. At baseline, BPH2/J exhibited significantly higher BP when compared to normotensive controls (BPN=123.9±5.3 vs. BPH=153.4±3.4 mmHg; n=4 p<0.05). Further, chronic delivery of ICV-TRV showed a higher magnitude of BP reduction in the BPH2/J group compared to controls (BPN=-3.8±3.0 vs. BPH=-8.8±1.3 mmHg; n=4 p<0.05), suggesting that the effects of b-arrestin activation are predominant under hypertensive states. Overall, endogenous ARRB2 counterbalances the deleterious effects of AT1R overactivation in the brain. The stimulation of the AT1R β-arrestin axis in the brain using biased AT1R agonist that penetrate the brain-blood barrier might be a potential strategy to treat low renin hypertension. HL084207 and HL144807 to CDS, and 22PRE898004 to NMM This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.