Ingolfsland Ellen C, Molomjamts Mandkhai, Foster Ann, Lee Haeyeon, Roehrich Heidi, Morikuni Amelia, Qureishy Husaam, Tran Phu V, McLoon Linda K, Georgieff Michael K
Department of Pediatrics, Division of Neonatology, University of Minnesota Medical School, Minneapolis, MN, USA.
Department of Ophthalmology and Visual Neurosciences, University of Minnesota Medical School, Minneapolis, MN, USA.
Pediatr Res. 2025 Feb;97(3):1237-1245. doi: 10.1038/s41390-024-03477-w. Epub 2024 Oct 8.
Phlebotomy-induced-anemia (PIA), which induces tissue hypoxia and angiogenesis, occurs universally among infants at risk for severe retinopathy of prematurity (ROP). We hypothesized that PIA exacerbates pathologic retinal neovascularization in ROP.
We induced PIA to a hematocrit of 18% among rats undergoing the established 50/10 oxygen-induced retinopathy (OIR) model. Rats were euthanized at P15 and P20, during the avascular and neovascular phases of OIR, respectively. Retinal vascular morphometry, cytokine/chemokine concentrations, transcriptomes, and mRNA expression of angiogenic and iron-deficiency markers were compared to non-PIA controls.
In OIR, PIA decreased percent avascular area at P15 by 35%, percent neovascular area at P20 by 42%, and select pro-inflammatory cytokine/chemokine concentrations at both time points. At P20, PIA increased mRNA expression of angiopoietin 2/ vascular endothelial growth factor-A 2-fold and transferrin and transferrin receptor 5-fold. RNA sequencing showed dampened pathways of angiogenesis, inflammation, and neural development in anemic OIR females.
Contrary to our hypothesis, PIA decreased OIR severity and retinal cytokine and chemokine levels and dampened transcriptomic pathways central to retinal vascular and neural development in neonatal rats. These data suggest PIA provides a protective effect from OIR. Further investigation into the functional effect of these molecular changes is warranted.
This is the first preclinical study to investigate the impact of neonatal anemia on oxygen-induced retinopathy (OIR) outcomes. This study adds to the literature that anemia decreases neovascularization, decreases cytokine and chemokine levels, and dampens angiogenic and neural transcriptomic pathways in the rat 50/10 OIR model. The study identifies a sex-specific transcriptomic response to anemia in the 50/10 OIR model, with females primarily impacted.
放血诱导性贫血（PIA）可导致组织缺氧和血管生成，在有发生严重早产儿视网膜病变（ROP）风险的婴儿中普遍存在。我们推测PIA会加重ROP中的病理性视网膜新生血管形成。
在已建立的50/10氧诱导性视网膜病变（OIR）模型的大鼠中，我们将PIA诱导至血细胞比容为18%。大鼠分别在OIR的无血管期和新生血管期的P15和P20时安乐死。将视网膜血管形态学、细胞因子/趋化因子浓度、转录组以及血管生成和缺铁标志物的mRNA表达与非PIA对照组进行比较。
在OIR中，PIA使P15时的无血管面积百分比降低了35%，P20时的新生血管面积百分比降低了42%，并且在两个时间点均降低了特定促炎细胞因子/趋化因子的浓度。在P20时，PIA使血管生成素2/血管内皮生长因子-A的mRNA表达增加了2倍，转铁蛋白和转铁蛋白受体增加了5倍。RNA测序显示贫血的OIR雌性大鼠中血管生成、炎症和神经发育的途径受到抑制。
与我们的假设相反，PIA降低了OIR的严重程度以及视网膜细胞因子和趋化因子水平，并抑制了新生大鼠视网膜血管和神经发育的核心转录组途径。这些数据表明PIA对OIR具有保护作用。有必要对这些分子变化的功能效应进行进一步研究。
这是第一项研究新生儿贫血对氧诱导性视网膜病变（OIR）结果影响的临床前研究。该研究补充了文献，表明贫血会减少新生血管形成，降低细胞因子和趋化因子水平，并抑制大鼠50/10 OIR模型中的血管生成和神经转录组途径。该研究确定了50/10 OIR模型中对贫血的性别特异性转录组反应，主要影响雌性。
