Shariatzadeh Mahnaz, Payán-Gómez César, Kzhyshkowska Julia, Dik Willem A, Leenen Pieter J M
Department of Immunology, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands.
Academic Direction, Universidad Nacional de Colombia, Sede de La Paz, Cesar 202010, Colombia.
Int J Mol Sci. 2025 May 19;26(10):4846. doi: 10.3390/ijms26104846.
Angiogenesis plays a crucial role in solid tumor growth. Ischemia and inflammation induce various angiogenic mediators, and patient metabolic conditions importantly influence this process. Macrophages closely interact with the vascular system and regulate angiogenesis through pro/anti-angiogenic factors. Traditionally, pro-angiogenic activity has been attributed to M2-like macrophages. We question this, as recent evidence suggests that also M1-like macrophages can be pro-angiogenic. Therefore, the aim is to identify the pro/anti-angiogenic gene expression profiles of human polarized macrophages unbiasedly. We also examine the effect of hyperglycemia on angiogenic gene expression, reflecting its role in diabetes and other metabolic conditions. Bioinformatic analysis was performed on the angiogenesis-related gene expression profiles of CD14+ monocyte-derived M1(IFN-γ)- and M2(IL-4)-polarized macrophages. The top differentially expressed genes were selected for validation. Macrophages were generated in vitro and polarized to M1(IFN-γ) and M2(IL-4/IL-6) cells under standard/hyperglycemic conditions. After immunophenotypic confirmation, selected gene expression was quantified using qPCR. IL-4 and IL-6 induce distinct M2-like phenotypes with mixed pro/anti-angiogenic gene expression. Remarkably, IFN-γ stimulation also increases several pro-angiogenic genes. Hyperglycemia affects the angiogenic expression profile in both M1- and M2-like macrophages, although distinctive identities remain intact. The pro-angiogenic phenotype is not limited to M2-polarized macrophages. Both M1- and M2-like macrophages express complex pro/anti-angiogenic gene profiles, which are only mildly influenced by hyperglycemia.
血管生成在实体瘤生长中起着关键作用。缺血和炎症会诱导多种血管生成介质，并且患者的代谢状况对这一过程有重要影响。巨噬细胞与血管系统密切相互作用，并通过促血管生成/抗血管生成因子调节血管生成。传统上，促血管生成活性被归因于M2样巨噬细胞。我们对此提出质疑，因为最近的证据表明M1样巨噬细胞也可能具有促血管生成作用。因此，目的是无偏倚地鉴定人极化巨噬细胞的促血管生成/抗血管生成基因表达谱。我们还研究了高血糖对血管生成基因表达的影响，以反映其在糖尿病和其他代谢状况中的作用。对CD14 +单核细胞衍生的M1（IFN-γ）和M2（IL-4）极化巨噬细胞的血管生成相关基因表达谱进行了生物信息学分析。选择差异表达最显著的基因进行验证。巨噬细胞在体外生成，并在标准/高血糖条件下极化为M1（IFN-γ）和M2（IL-4 / IL-6）细胞。在进行免疫表型确认后，使用qPCR对选定的基因表达进行定量。IL-4和IL-6诱导具有混合促血管生成/抗血管生成基因表达的不同M2样表型。值得注意的是，IFN-γ刺激也会增加几种促血管生成基因。高血糖会影响M1样和M2样巨噬细胞中的血管生成表达谱，尽管其独特特征仍然存在。促血管生成表型并不局限于M2极化巨噬细胞。M1样和M2样巨噬细胞均表达复杂的促血管生成/抗血管生成基因谱，且仅受到高血糖的轻微影响。
