Bevacizumab De-Escalating Doses and VEGF-A/AGT Gene Expression

This study explores the cellular mechanisms of low-dose anti-VEGF therapy for retinopathy of prematurity (ROP) and its severe form, plus disease. The research specifically examines the expression of VEGF-A and angiotensinogen (AGT) genes in retinal pigment epithelium (RPE) cells under hypoxic conditions, mimicking ROP. RPE cells were treated with varying doses of bevacizumab (312.5 µg/mL to 4.9 µg/mL), and gene expression was analyzed. Hypoxia decreased AGT expression by 0.5-fold and increased VEGF-A expression by 1.5-fold. Interestingly, bevacizumab doses below 39.1 µg/mL significantly upregulated AGT, while the lowest dose (4.9 µg/mL) unexpectedly increased VEGF-A. Bioinformatics analysis highlighted VEGFA as a central hub in the direct interaction network, while AGT exhibited notable bottleneck properties within the broader hypoxia‑associated network. The findings suggest that bevacizumab concentrations between 19.5 and 9.8 μg/mL are optimal for ROP treatment. This range stabilizes VEGF-A expression while potentially reducing plus disease by increasing AGT expression, underscoring the critical need for precise dose optimization in ROP therapy.本研究探讨了早产儿视网膜病变（retinopathy of prematurity, ROP）及其重症形式——Plus型病变的低剂量抗血管内皮生长因子（anti-VEGF）治疗的细胞机制。本研究聚焦于模拟ROP病理状态的缺氧环境下，视网膜色素上皮（retinal pigment epithelium, RPE）细胞中血管内皮生长因子A（VEGF-A）与血管紧张素原（angiotensinogen, AGT）的基因表达情况。实验中，研究人员采用梯度剂量的贝伐珠单抗（浓度范围为312.5 μg/mL至4.9 μg/mL）处理RPE细胞，并对其基因表达水平进行了检测分析。 缺氧环境可使AGT的表达量降至原水平的0.5倍，同时使VEGF-A的表达量升高1.5倍。值得关注的是，剂量低于39.1 μg/mL的贝伐珠单抗可显著上调AGT的表达，而最低剂量组（4.9 μg/mL）则意外地促进了VEGF-A的表达。生物信息学分析结果显示，VEGFA在直接相互作用网络中充当核心枢纽节点，而AGT在更广范围的缺氧相关调控网络中表现出显著的瓶颈特性。 本研究结果表明，贝伐珠单抗浓度介于9.8 μg/mL至19.5 μg/mL之间时，为ROP治疗的最优剂量区间。该剂量区间可稳定VEGF-A的表达水平，并通过上调AGT的表达潜在抑制Plus型病变的发生发展，这凸显了ROP治疗中实施精准剂量优化的关键必要性。