MT2A promotes angiogenesis in chronically ischemic brains through a copper–mitochondria regulatory mechanism

作者：Ni Mo, Chuyang Tai, Yang Yang, Cong Ling, Baoyu Zhang, Lei Wei, Cian Yao, Hui Wang, Chuan Chen · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-025-06163-5 · 被引用次数：17 · 研究领域：Trace Elements in Health、Ferroptosis and cancer prognosis、Alzheimer's disease research and treatments

Approximately half of patients with chronic ischemic cerebrovascular disease (CICD) exhibit poor revascularization. Metallothionein 2 A (MT2A) has a high affinity for metal ions and is potentially capable of chelating toxic copper ions to alleviate the impairment of angiogenesis. Therefore, we hypothesized that MT2A could promote angiogenesis in chronically ischemic brains by neutralizing excessive copper ions during copper overload (CPO). We first collected dura matter (DM) samples from CICD patients and examined the expression of cuproptosis-related genes (DLAT, FDX1, and SDHB) to confirm the inhibitory effect of CPO on angiogenesis. Then, we treated human umbilical vein endothelial cells (HUVECs) with different concentrations of elesclomol and CuCl 2 to determine the optimal concentration for inducing CPO. HUVEC activity and mitochondrial structure and function were detected to explore the ability of MT2A to alleviate CPO-induced damage. Finally, a rat model of 2-vessel occlusion plus encephalo-myo-synangiosis (2VO + EMS) with CPO was established to test the proangiogenic effect of MT2A through the copper–mitochondria regulatory mechanism in chronically ischemic brains. Compared with those from Matsushima grade A patients, DM samples from Matsushima grade C patients presented significantly greater DLAT and FDX1 expression and significantly lower SDHB expression. The optimal drug concentration for inducing CPO was subsequently determined, and in vitro experiments revealed t...