(A) Left: Schematic showing that H₂O₂ generated by DAAO expressed in the vascular endothelium promotes oxidative stress throughout the vascular wall of d-alanine–fed DAAO-TG^Tie2 transgenic mice (Figure 3). Right: Schematic of the signaling pathways initiated by the chemogenetic generation of H₂O₂ in vascular endothelial cells that lead ultimately to systemic hypertension and aortic aneurysm formation (Figure 1). H₂O₂ directly promotes ASK1 oxidation and autophosphorylation, which leads to the subsequent phosphorylation of MEK7 and JNK1 (52–57). The phosphoprotein phosphatase DUSP3 is present in abdominal but not thoracic VSMCs (Figure 6) and catalyzes the dephosphorylation of JNK1 (49), which is permissive for KLF4 translocation and leads to VSMC phenotypic switching (50). (B and C) Vascular phenotype of alanine-fed DAAO-TG^Tie2 and control mice treated with the small-molecule DUSP3 inhibitor MLS-0437605 (DUSP3-I; 4 mg/kg/d by daily oral gavage) for 3 months. (B) Measurements of abdominal aorta diameter, showing that DUSP3-I treatment completely blocks the formation of aortic aneurysms in d-alanine–fed DAAO-TG^Tie2 mice. (C) Systolic blood pressure measurements in control and DAAO-TG^Tie2 transgenic mice after 3 months of drug plus d-alanine treatment, showing that DUSP3-I attenuates the increase in blood pressure seen in the d-alanine–fed DAAO-TG^Tie2 mice that were not treated with DUSP3-I. There was a small but statistically significant increase in blood pressure comparing the L-alanine-fed DAAO-TGTie2 and the mice fed D-alanine plus DUSP3-I. n = 3 mice in each treatment group. *P < 0.05, **P < 0.01, ***P < 0.001, multiple 2-tailed Student’s t tests and ANOVA performed for multiple comparisons. Data are presented as means ± SEM of at least 3 independent experiments.