Ren Ling, Zhang Linyu, Bai Yun, Huang Chang, Li Xiaosa, Ma Fanfei, Mu Wan, Yao Mudi, Jiang Chang, Chen Xiangjun, Jiang Qin, Yan Biao
Department of Ophthalmology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200080, China.
Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, 200030, China.
Adv Sci (Weinh). 2025 Jun 23:e17045. doi: 10.1002/advs.202417045.
Diabetes is a prevalent metabolic disorder, and its associated microvascular dysfunction plays a key role in the pathogenesis of complications such as retinopathy, nephropathy, and peripheral vascular disease. However, the mechanism governing metabolic regulation and functional heterogeneity of endothelial dysfunction remains incompletely understood. This study investigates the role of metabolic stress-induced activation of choline kinase α (CHKA) in endothelial cell (EC) subpopulations, contributing to diabetes-induced microvascular dysfunction. Using single-cell RNA sequencing (scRNA-seq), three distinct EC subclusters are identified within retinal vessels. Among them, one subcluster characterized by elevated CHKA expression is associated with enhanced angiogenic activity. CHKA silencing in ECs inhibited angiogenic effects and reduced retinal vascular dysfunction in diabetic murine models. CHKA silencing also disrupted NAD metabolism, causing reduced NAD levels. Supplementation with nicotinamide mononucleotide (NMN), a precursor of NAD, partially reversed the anti-angiogenic effects induced by CHKA silencing. Mechanistically, CHKA regulated endothelial dysfunction through the NAD-SIRT1-Notch signaling. Clinical sample analysis and Mendelian randomization studies provided strong evidence linking increased CHKA expression with diabetic microvascular complications. Collectively, this study advances the understanding of endothelial heterogeneity and identifies CHKA as a critical regulator of pathological angiogenesis, highlighting its potential as a therapeutic target for diabetic vascular complications.
糖尿病是一种常见的代谢紊乱疾病，其相关的微血管功能障碍在视网膜病变、肾病和外周血管疾病等并发症的发病机制中起关键作用。然而，代谢调节和内皮功能障碍功能异质性的调控机制仍未完全明确。本研究调查了代谢应激诱导的胆碱激酶α（CHKA）激活在内皮细胞亚群中的作用，这一作用导致了糖尿病诱导的微血管功能障碍。利用单细胞RNA测序（scRNA-seq），在视网膜血管中鉴定出三个不同的内皮细胞亚群。其中，一个以CHKA表达升高为特征的亚群与增强的血管生成活性相关。在内皮细胞中沉默CHKA可抑制血管生成作用，并减轻糖尿病小鼠模型中的视网膜血管功能障碍。CHKA沉默还破坏了NAD代谢，导致NAD水平降低。补充烟酰胺单核苷酸（NMN），一种NAD的前体，部分逆转了CHKA沉默诱导的抗血管生成作用。从机制上讲，CHKA通过NAD-SIRT1-Notch信号通路调节内皮功能障碍。临床样本分析和孟德尔随机化研究提供了强有力的证据，将CHKA表达增加与糖尿病微血管并发症联系起来。总体而言，本研究增进了对内皮异质性的理解，并确定CHKA是病理性血管生成的关键调节因子，突出了其作为糖尿病血管并发症治疗靶点的潜力。
