School of Life Sciences, Nantong Laboratory of Development and Diseases, Nantong University, Nantong, China.
Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.
Cardiovasc Res. 2024 Jul 31;120(9):1065-1080. doi: 10.1093/cvr/cvae085.
In patients with diabetic microvascular complications, decreased perfusion or vascular occlusion, caused by reduced vascular diameter, is a common characteristic that will lead to insufficient blood supply. Yet, the regulatory mechanism and effective treatment approach remain elusive.
Our initial findings revealed a notable decrease in the expression of human AQP1 in both diabetic human retina samples (49 healthy vs. 54 diabetic samples) and high-glucose-treated human retinal microvascular endothelial cells. Subsequently, our investigations unveiled a reduction in vascular diameter and compromised perfusion within zebrafish embryos subjected to high glucose treatment. Further analysis indicated a significant down-regulation of two aquaporins, aqp1a.1 and aqp8a.1, which are highly enriched in ECs and are notably responsive to hyperglycaemic conditions. Intriguingly, the loss of function of aqp1a.1 and/or aqp8a.1 resulted in a reduction of intersegmental vessel diameters, effectively mirroring the phenotype observed in the hyperglycaemic zebrafish model. The overexpression of aqp1a.1/aqp8a.1 in zebrafish ECs led to notable enlargement of microvascular diameters. Moreover, the reduced vessel diameters resulting from high-glucose treatment were effectively rescued by the overexpression of these aquaporins. Additionally, both aqp1a.1 and apq8a.1 were localized in the intracellular vacuoles in cultured ECs as well as the ECs of sprouting ISVs, and the loss of Aqps caused the reduction of those vacuoles, which was required for lumenization. Notably, while the loss of AQP1 did not impact EC differentiation from human stem cells, it significantly inhibited vascular formation in differentiated ECs.
EC-enriched aquaporins regulate the diameter of blood vessels through an intracellular vacuole-mediated process under hyperglycaemic conditions. These findings collectively suggest that aquaporins expressed in ECs hold significant promise as potential targets for gene therapy aimed at addressing vascular perfusion defects associated with diabetes.
在患有糖尿病微血管并发症的患者中，由于血管直径减小导致的灌注减少或血管闭塞是常见特征，这将导致血液供应不足。然而，其调节机制和有效治疗方法仍不明确。
我们的初步研究结果表明，在糖尿病患者的视网膜样本（49 例健康对照和 54 例糖尿病患者）和高糖处理的人视网膜微血管内皮细胞中，AQP1 的表达显著降低。随后，我们发现高糖处理的斑马鱼胚胎中血管直径减小，灌注受损。进一步的分析表明，两个水通道蛋白，aqp1a.1 和 aqp8a.1 的表达显著下调，这两种蛋白在 ECs 中高度富集，对高糖条件反应明显。有趣的是，aqp1a.1 和/或 aqp8a.1 的功能丧失导致节间血管直径减小，这与高糖斑马鱼模型中观察到的表型相似。在斑马鱼 ECs 中过表达 aqp1a.1/aqp8a.1 可显著增大微血管直径。此外，高糖处理导致的血管直径减小可通过过表达这些水通道蛋白得到有效挽救。此外，aqp1a.1 和 apq8a.1 在培养的 ECs 以及发芽 ISVs 的 ECs 中的细胞内空泡中定位，AQP 的缺失导致这些空泡减少，这是空泡化所必需的。值得注意的是，尽管 AQP1 的缺失并不影响人干细胞向 EC 的分化，但它显著抑制了分化后的 EC 中血管的形成。
高糖条件下，EC 丰富的水通道蛋白通过细胞内空泡介导的过程调节血管直径。这些发现表明，EC 中表达的水通道蛋白作为治疗糖尿病相关血管灌注缺陷的基因治疗的潜在靶点具有重要意义。
