Abstract Background Aquaporin-1 (AQP1) is the main aquaporin isoform in the CV system, abundantly expressed in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). We previously identified AQP1 as a key mediator of transmembrane hydrogen peroxide (H2O2) flux in cardiac myocytes and ECs, overturning the long-standing paradigm of passive H2O2 diffusion across biological membranes. Purpose Given the central role of redox signaling in nitric oxide (NO)–dependent endothelial dysfunction—a hallmark of all CV diseases—we hypothesized that AQP1 may modulate vascular tone by regulating NO-dependent relaxation under oxidative stress. Methods In Aqp1 KO mice and WT littermates, vascular homeostasis was assessed following angiotensin II (Ang II) infusion or physiological ageing. NO-dependent relaxations were measured in aortic rings using wire myography (DMT devices). Non-PEGylated catalase was used to probe the role of extracellular H2O2 and bulk RNA sequencing of Ang II–treated aortas identified AQP1-dependent molecular responses. Animal procedures complied with NIH 85-23 and national law. Results AQP1 was confirmed as the predominant vascular peroxiporin, expressed across the vascular wall and also in PVAT. Wire myography showed full preservation of NO-dependent relaxation in Aqp1 KO mice under Ang II challenge and during ageing, whereas WT vessels exhibited marked impairment. A similar protective effect was observed in Aqp1 KO PVAT aortic rings following Ang II exposure. Addition of non-PEGylated catalase enhanced NO-dependent vasorelaxation in WT but not in Aqp1 KO rings and improved acetylcholine-induced relaxation in Ang II–treated WT vessels, restoring endothelial responsiveness. Transcriptomic profiling of Aqp1 KO versus WT Ang II-treated aortas revealed broad suppression of redox-sensitive and profibrotic signaling (TGF-β/collagen, NF-κB, HIF-1α, Wnt, PI3K–Akt) with concomitant enhancement of NO-signaling and oxidative metabolism (oxidative phosphorylation, pentose phosphate pathway), consistent with improved endothelial resilience. Conclusion(s) These findings identify AQP1 as a central regulator of NO-dependent endothelial function through coordinated actions across the vasculature. They also reveal a pivotal role for extracellular H2O2 in driving NO-dependent endothelial dysfunction and open the way to investigating potential EC–PVAT synergistic interactions in ROS-dependent vascular function. Ex vivo myography and transcriptomic analyses demonstrate that Aqp1 deletion confers vascular protection by limiting pathological H2O2 influx, preserving NO-mediated relaxation and oxidative phosphorylation under ROS-challenging conditions, maintaining endothelial integrity and attenuating redox-sensitive inflammatory pathways. Together, these results position AQP1 as a key peroxiporin orchestrating redox–vascular crosstalk and highlight it as an attractive therapeutic target in oxidative stress–driven cardiovascular disease.Aorta NO-dependant relaxation.For image description, please refer to the figure legend and surrounding text. RNA-seq of AngII-treated aortasFor image description, please refer to the figure legend and surrounding text.
Dieu et al. (Fri,) studied this question.