Hypobaric hypoxia in plateau environments inevitably disrupts metabolic homeostasis and contributes to high-altitude diseases. Vascular endothelial cells play a crucial role in maintaining vascular homeostasis. However, it remains unclear whether hypoxia-mediated changes in energy metabolism compromise vascular system stability and function. Through integrated transcriptomic and targeted metabolomic analyses, we identified that hypoxia induces vascular endothelial dysfunction via energy metabolism dysregulation. Specifically, hypoxia drives a metabolic shift toward glycolysis over oxidative phosphorylation in vascular endothelial cells, resulting in excessive lactate production. This lactate overload triggers PKM2 lactylation, which stabilizes PKM2 by inhibiting ubiquitination, forming a feedforward loop that exacerbates mitochondrial collapse and vascular endothelial dysfunction. Importantly, blocking the pyruvate-lactate axis helps maintain the balance between glycolysis and oxidative phosphorylation, thereby protecting vascular endothelial function under hypoxic conditions. Our findings not only elucidate a novel mechanism underlying hypoxia-induced vascular damage but also highlight the pyruvate-lactate axis as a potential therapeutic target for preventing vascular diseases in both altitude-related and pathological hypoxia.

Endothelial dysfunction is a common complication of diabetes mellitus (DM) and contributes to the high incidence and mortality of cardiovascular and cerebrovascular diseases. Aberrant epigenetic regulation under diabetic conditions, including histone modifications, DNA methylation, and non-coding RNAs (ncRNAs) play key roles in the initiation and progression of diabetic vascular complications. ASH2L, a H3K4me3 regulator, triggers genetic transcription, which is critical for physiological and pathogenic processes. In this study we investigated the role of ASH2L in mediating diabetic endothelial dysfunction. We showed that ASH2L expression was significantly elevated in vascular tissues from diabetic db/db mice and in rat aortic endothelial cells (RAECs) treated with high glucose medium (11 and 22 mM). Knockdown of ASH2L in RAECs markedly inhibited the deteriorating effects of high glucose, characterized by reduced oxidative stress and inflammatory responses. Deletion of endothelial ASH2L in db/db mice by injection of an adeno-associated virus (AAV)-endothelial specific system carrying shRNA against Ash2l (AAV-shAsh2l) restored the impaired endothelium-dependent relaxations, and ameliorated DM-induced vascular dysfunction. We revealed that ASH2L expression activated reductase STEAP4 transcription in vitro and in vivo, which consequently elevated Cu(I) transportation into ECs by the copper transporter CTR1. Excess copper produced by STEAP4-mediated copper uptake triggered oxidative stress and inflammatory responses, resulting in endothelial dysfunction. Our results demonstrate that hyperglycemia triggered ASH2L-STEAP4 axis contributes to diabetic endothelial dysfunction by modulating copper uptake into ECs and highlight the therapeutic potential of blocking the endothelial ASH2L in the pathogenesis of diabetic vascular complications.

A new lignan glycoside, (7S,8R)-guaiacylglycerol-ferulic acid ether-7-O-β-D-glucopyranoside (1), along with five known phenylpropanoids (2–6) and seven phenylpropanoid glycosides (7–13), were isolated from the stems of Zanthoxylum armatum DC. Their structures were elucidated by spectroscopic analysis. Compounds 2–8 and 11–13 were first isolated from Rutaceae and the others were isolated for the first time from Z. armatum.

Two new phenolic glycoside, 2-methoxy-4-hydroxylphenyl-1-O-α-L-rhamnopyranosyl- (1″ → 6′)-β-D-glucopyranoside. (1) and threo-3-methoxy-5-hydroxy-phenylpropanetriol-8-O-β-D-glucopyranoside (2), were isolated from the stems of Zanthoxylum armatum. The compounds 1 and 2 showed weak scavenging activity in DPPH free radical assay with IC₅₀ values of 323 and 114 mM, respectively.