Boeck Myriam, Yagi Hitomi, Lundgren Pia, Pivodic Aldina, Nilsson Anders K, Zeng Yan, Chen Chuck T, Kasai Taku, Lee Deokho, Nian Shen, Hirst Victoria, Neilsen Katherine, Wang Chaomei, Lee Jeff, Yu Mathew, McCutcheon Andrew, Singh Sasha A, Aikawa Masanori, Bazinet Richard P, Fu Zhongjie, Hellström Ann, Smith Lois Eh
Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Ophthalmology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Pharmacol Res. 2025 Sep;219:107877. doi: 10.1016/j.phrs.2025.107877. Epub 2025 Jul 23.
Retinopathy of prematurity (ROP) with early vessel loss (Phase I) followed by uncontrolled vessel growth (Phase II) causes visual impairment in premature infants. Although supplementation with omega-3 (n-3) docosahexaenoic acid (DHA) alone shows mixed results in preventing ROP, supplementation with both n-3 DHA and n-6 arachidonic acid (ARA) in early postnatal life reduces severe ROP by 50 % (Mega Donna Mega study). In the Mega Donna Mega study, 146 (72.6 %) of 201 included infants had at least one hyperglycemic episode during the first 14 days of life, which is a strong ROP risk factor. We therefore evaluated the protective effects and mechanisms of combined dietary n-3 DHA and n-6 ARA in a neonatal mouse model of hyperglycemia-induced suppression of retinal vascular development (Phase I ROP). At postnatal day (P) 10, retinal vessel growth was improved in pups from mothers on diets enriched with 1 % DHA + 2 % ARA vs. 3 % DHA. Lipid changes in pup plasma and RPE complex (retinal pigment epithelium with choroid and sclera) were in accordance with maternal diets' DHA and ARA levels, indicating that milk lipids reflected maternal diets. Proteomic retinal analysis revealed increased abundances of proteins related to mitochondrial respiration and glucose metabolism with the combined diet. Inhibition of mitochondrial ATP synthase negated the protective effects of the combined diet. In conclusion, combined DHA+ARA oral maternal supplementation protects against hyperglycemia-induced retinopathy in mouse neonates (Phase I ROP model) through enhanced retinal metabolism, suggesting the potential of balanced lipid supplementation for ROP prevention.
早产儿视网膜病变（ROP）先出现早期血管缺失（I期），随后是血管生长失控（II期），可导致早产儿视力受损。尽管单独补充ω-3（n-3）二十二碳六烯酸（DHA）在预防ROP方面的结果不一，但在出生后早期同时补充n-3 DHA和n-6花生四烯酸（ARA）可使严重ROP减少50%（Mega Donna Mega研究）。在Mega Donna Mega研究中，纳入的201例婴儿中有146例（72.6%）在出生后的前14天内至少有一次高血糖发作，这是一个很强的ROP危险因素。因此，我们在高血糖诱导的视网膜血管发育抑制（I期ROP）的新生小鼠模型中评估了联合膳食n-3 DHA和n-6 ARA的保护作用及机制。在出生后第10天，与摄入3% DHA的母鼠所生幼崽相比，摄入富含1% DHA + 2% ARA饮食的母鼠所生幼崽的视网膜血管生长得到改善。幼崽血浆和视网膜色素上皮复合体（视网膜色素上皮与脉络膜和巩膜）中的脂质变化与母鼠饮食中的DHA和ARA水平一致，表明乳汁中的脂质反映了母鼠的饮食。视网膜蛋白质组分析显示，联合饮食使与线粒体呼吸和葡萄糖代谢相关的蛋白质丰度增加。抑制线粒体ATP合酶可消除联合饮食的保护作用。总之，母鼠口服联合补充DHA+ARA可通过增强视网膜代谢来预防新生小鼠的高血糖诱导性视网膜病变（I期ROP模型），这表明均衡补充脂质在预防ROP方面具有潜力。
