IDH基因中的增强功能突变导致(D)-2-羟基戊二酸(D-2HG)的过度产生，从而固有地改变肿瘤细胞的表观遗传学，并通过非表观遗传通路对周围的非癌细胞产生影响。然而，D-2HG是否对肿瘤微环境中的内皮细胞具有旁分泌作用需要进一步澄清。我们通过免疫组织化学在60例高级别星形胶质瘤的组织切片中定量了微血管密度，其中包括IDH突变和未突变的肿瘤。发现携带IDH突变的肿瘤中的微血管密度降低。离体实验显示，D-2HG通过抑制细胞增殖而不是细胞存活来抑制内皮细胞的迁移、伤口愈合和管形成，可能通过降低mTOR/STAT3信号通路的激活来实现。此外，D-2HG通过增加联合蛋白的表达，从而集体增加内皮细胞的屏障功能，降低了荧光二聚体的渗透性和抑制细胞间T细胞经内皮细胞转移。这些结果表明，D-2HG可以通过降低肿瘤内血管密度和抑制代谢物的转运以及循环细胞的渗出进一步影响肿瘤血管微环境。这些观察结果为将IDH抑制与抗肿瘤免疫/血管生成方法相结合提供了理论基础，并且为那些表达突变IDH等位基因的病人耐受抗血管生成药物的分子基础提供了线索。© 作者2023. 由牛津大学出版社代表美国神经病理学家协会发表。版权所有。如需授权，请发送电子邮件至：journals.permissions@oup.com。

Gain-of-function mutations in isocitrate dehydrogenase (IDH) genes result in excessive production of (D)-2-hydroxyglutarate (D-2HG) which intrinsically modifies tumor cell epigenetics and impacts surrounding noncancerous cells through nonepigenetic pathways. However, whether D-2HG has a paracrine effect on endothelial cells in the tumor microenvironment needs further clarification. We quantified microvessel density by immunohistochemistry using tissue sections from 60 high-grade astrocytic gliomas with or without IDH mutation. Microvessel density was found to be reduced in tumors carrying an IDH mutation. Ex vivo experiments showed that D-2HG inhibited endothelial cell migration, wound healing, and tube formation by suppressing cell proliferation but not viability, possibly through reduced activation of the mTOR/STAT3 pathway. Further, D-2HG reduced fluorescent dextran permeability and decreased paracellular T-cell transendothelial migration by augmenting expression of junctional proteins thereby collectively increasing endothelial barrier function. These results indicate that D-2HG may influence the tumor vascular microenvironment by reducing the intratumoral vasculature density and by inhibiting the transport of metabolites and extravasation of circulating cells into the astrocytoma microenvironment. These observations provide a rationale for combining IDH inhibition with antitumor immunological/angiogenic approaches and suggest a molecular basis for resistance to antiangiogenic drugs in patients whose tumors express a mutant IDH allele.© The Author(s) 2023. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.