Qambari Hassanain, Yu Paula K, Balaratnasingam Chandrakumar, Dickson Jayden, Yu Dao-Yi
Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, Australia.
Lions Eye Institute, The University of Western Australia, 2 Verdun Street, Nedlands, Perth, WA, 6009, Australia.
Sci Rep. 2025 Aug 20;15(1):30559. doi: 10.1038/s41598-025-12612-4.
Endothelial dysfunction is a known consequence of chronic hyperglycemia and a major pathogenic factor for microvascular diseases such as diabetic retinopathy. The effect and exposure period to acute hyperglycemia on the vascular endothelium, and its ability to recover from such exposure is less well understood. Here, we used an isolated perfused eye preparation to study the effect of acute hyperglycemia on the ocular microvascular endothelium of normoglycemic and 1-, 2-, 3-, and 4-week streptozotocin (STZ)-induced diabetic rats. The acetylcholine (Ach)-induced vasodilatory response was measured during sequential exposure to 6 mM (normoglycemic), 12 mM (mild hyperglycemic), 24 mM (hyperglycemic) and then again to 6 mM (normoglycemic) perfusates. Eyes were then processed histologically for examination of capillary density, capillary diameter, pericyte distribution, endothelial nitric oxide synthase (eNOS) distribution and accumulation of advanced glycated end products (AGEs). Ach responses were significantly enhanced in normoglycemic, 1-,2-, 3- and 4-week diabetic eyes after less than 2-h of high glucose (24 mM) exposure. Upon return to normoglycemia, Ach-induced responses in 1-, 2- and 3-week diabetic eyes were comparable with normoglycemic eyes. In the 4-week diabetic eyes, Ach-induced vasodilatory responses remained significantly enhanced despite restoration of normoglycemia. Capillary density and capillary diameter did not change significantly after 1-, 2-, 3- and 4-weeks of STZ-induced diabetes. Pericyte distribution significantly increased in all vascular layers of the 3- and 4-week diabetic eyes. eNOS immunoreactivity significantly increased in 1-week diabetic eyes. Significant AGEs immunolabelling was detected in the vascular basement membrane and intracellularly in 1-week STZ rats. These findings suggest that whilst endothelial function can recover after short term hyperglycemia, prolonged exposure (≥ 4 weeks) results in incomplete restoration, indicating a potential transition towards irreversible dysfunction.
内皮功能障碍是慢性高血糖已知的后果，也是糖尿病视网膜病变等微血管疾病的主要致病因素。急性高血糖对血管内皮的影响、暴露时间及其从这种暴露中恢复的能力尚不太清楚。在此，我们使用离体灌注眼标本，研究急性高血糖对正常血糖以及1、2、3和4周链脲佐菌素（STZ）诱导的糖尿病大鼠眼微血管内皮的影响。在依次暴露于6 mM（正常血糖）、12 mM（轻度高血糖）、24 mM（高血糖）然后再次暴露于6 mM（正常血糖）灌注液期间，测量乙酰胆碱（Ach）诱导的血管舒张反应。然后对眼睛进行组织学处理，以检查毛细血管密度、毛细血管直径、周细胞分布、内皮型一氧化氮合酶（eNOS）分布以及晚期糖基化终末产物（AGEs）的积累。在高糖（24 mM）暴露不到2小时后，正常血糖、1、2、3和4周糖尿病眼的Ach反应显著增强。恢复正常血糖后，1、2和3周糖尿病眼的Ach诱导反应与正常血糖眼相当。在4周糖尿病眼中，尽管恢复了正常血糖，Ach诱导的血管舒张反应仍显著增强。STZ诱导糖尿病1、2、3和4周后，毛细血管密度和毛细血管直径没有显著变化。3和4周糖尿病眼的所有血管层中周细胞分布显著增加。1周糖尿病眼中eNOS免疫反应性显著增加。在1周STZ大鼠的血管基底膜和细胞内检测到显著的AGEs免疫标记。这些发现表明，虽然短期高血糖后内皮功能可以恢复，但长期暴露（≥4周）会导致恢复不完全，表明可能向不可逆功能障碍转变。
