Retinopathy of prematurity (ROP) is a blinding aberrancy of retinal vascular maturation in preterm infants. Despite delayed onset after preterm birth, representing a window for therapeutic intervention, we cannot prevent or cure ROP blindness. A natural form of ROP protection exists in the setting of early-onset maternal preeclampsia, though is not well characterized. As ischemia is a central feature in both ROP and preeclampsia, we hypothesized that angiogenesis mediators may underlie this protection. To test our hypothesis we analyzed peripheral blood expression of candidate proteins with suggested roles in preeclamptic and ROP pathophysiology and with a proposed angiogenesis function (HTRA-1, IGF-1, TGFβ-1, and VEGF-A). Analysis in a discovery cohort of 40 maternal-infant pairs found that elevated HTRA-1 (high-temperature requirement-A serine peptidase-1) was significantly associated with increased risk of ROP and the absence of preeclampsia, thus fitting a model of preeclampsia-mediated ROP protection. We validated these findings and further demonstrated a dose-response between systemic infant HTRA-1 expression and risk for ROP development in a larger and more diverse validation cohort consisting of preterm infants recruited from two institutions. Functional analysis in the oxygen-induced retinopathy (OIR) murine model of ROP supported our systemic human findings at the local tissue level, demonstrating that HtrA-1 expression is elevated in both the neurosensory retina and retinal pigment epithelium by RT-PCR in the ROP disease state. Finally, transgenic mice over-expressing HtrA-1 demonstrate greater ROP disease severity in this model. Thus, HTRA-1 may underlie ROP protection in preeclampsia and represent an avenue for disease prevention, which does not currently exist.

早产儿视网膜病变（ROP）是早产儿视网膜血管成熟的致盲异常。尽管早产后发病延迟，这代表了治疗干预的窗口，但我们无法预防或治愈ROP失明。ROP保护的自然形式存在于早发的母亲先兆子痫的环境中，尽管其特征尚不清楚。由于缺血是ROP和先兆子痫的主要特征，因此我们假设血管生成介质可能是这种保护作用的基础。为了检验我们的假设，我们分析了候选蛋白的外周血表达，这些蛋白在先兆子痫和ROP病理生理中具有建议的作用，并具有拟议的血管生成功能（HTRA-1，IGF-1，TGFβ-1和VEGF-A）。在对40个母婴对的发现队列中进行的分析发现，升高的HTRA-1（高温需求-A丝氨酸肽酶-1）与ROP风险增加和先兆子痫不存在显着相关，因此适合先兆子痫-介导的ROP保护。我们验证了这些发现，并进一步证实了系统性婴儿HTRA-1表达与ROP发育风险之间的剂量反应，该人群由两个机构招募的早产儿组成，且规模更大，种类繁多。ROP的氧诱导性视网膜病（OIR）小鼠模型中的功能分析支持了我们在局部组织水平上的系统性人类研究结果，表明ROP中的RT-PCR显示HtrA-1在神经感觉视网膜和视网膜色素上皮细胞中的表达均升高疾病状态。最后，在该模型中，过表达HtrA-1的转基因小鼠表现出更高的ROP疾病严重性。因此，HTRA-1可能在先兆子痫中成为ROP保护的基础，并代表疾病的途径预防，目前不存在。