Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults. Vascular pericyte degeneration is the predominant clinical manifestation of DR, yet the mechanism governing pericyte degeneration is poorly understood. Circular RNAs (circRNAs) play important roles in multiple biological processes and disease progression. Here, we investigated the role of circRNA in pericyte biology and diabetes-induced retinal vascular dysfunction. cZNF532 expression was upregulated in pericytes under diabetic stress, in the retinal vessels of a diabetic murine model, and in the vitreous humor of diabetic patients. cZNF532 silencing reduced the viability, proliferation, and differentiation of pericytes and suppressed the recruitment of pericytes toward endothelial cells in vitro. cZNF532 regulated pericyte biology by acting as a miR-29a-3p sponge and inducing increased expression of NG2, LOXL2, and CDK2. Knockdown of cZNF532 or overexpression of miR-29a-3p aggravated streptozotocin-induced retinal pericyte degeneration and vascular dysfunction. By contrast, overexpression of cZNF532 or inhibition of miR-29a-3p ameliorated human diabetic vitreous–induced retinal pericyte degeneration and vascular dysfunction. Collectively, these data identify a circRNA-mediated mechanism that coordinates pericyte biology and vascular homeostasis in DR. Induction of cZNF532 or antagonism of miR-29a-3p is an exploitable therapeutic approach for the treatment of DR.

Rationale: Current treatments for ocular angiogenesis primarily focus on blocking the activity of vascular endothelial growth factor (VEGF), but unfavorable side effects and unsatisfactory efficacy remain issues. The identification of novel targets for anti-angiogenic treatment is still needed.

Introduction: Diabetic macular edema (DME) is a major cause of vision impairment in the patients with diabetes. Optical Coherence Tomography (OCT) is an important ophthalmic imaging method, which can enable early detection of DME. However, it is difficult to achieve high-efficiency and high-precision extraction of DME in OCT images because the sources of OCT images are diverse and the quality of OCT images is not stable. Thus, it is still required to design a model to improve the accuracy of DME extraction in OCT images.Methods: A lightweight model (DME-DeepLabV3+) was proposed for DME extraction using a DeepLabV3+ architecture. In this model, MobileNetV2 model was used as the backbone for extracting low-level features of DME. The improved ASPP with sawtooth wave-like dilation rate was used for extracting high-level features of DME. Then, the decoder was used to fuse and refine low-level and high-level features of DME. Finally, 1711 OCT images were collected from the Kermany dataset and the Affiliated Eye Hospital. 1369, 171, and 171 OCT images were randomly selected for training, validation, and testing, respectively.Conclusion: In ablation experiment, the proposed DME-DeepLabV3+ model was compared against DeepLabV3+ model with different setting to evaluate the effects of MobileNetV2 and improved ASPP on DME extraction. DME-DeepLabV3+ had better extraction performance, especially in small-scale macular edema regions. The extraction results of DME-DeepLabV3+ were close to ground truth. In comparative experiment, the proposed DME-DeepLabV3+ model was compared against other models, including FCN, UNet, PSPNet, ICNet, and DANet, to evaluate DME extraction performance. DME-DeepLabV3+ model had better DME extraction performance than other models as shown by greater pixel accuracy (PA), mean pixel accuracy (MPA), precision (Pre), recall (Re), F1-score (F1), and mean Intersection over Union (MIoU), which were 98.71%, 95.23%, 91.19%, 91.12%, 91.15%, and 91.18%, respectively.Discussion: DME-DeepLabV3+ model is suitable for DME extraction in OCT images and can assist the ophthalmologists in the management of ocular diseases.

Diabetic vasculopathy, encompassing complications such as diabetic retinopathy, represents a significant source of morbidity, with inflammation playing a pivotal role in the progression of these complications. This study investigates the influence of N6-methyladenosine demethylase (m6A) modification and the m6A demethylase fat mass and obesity-associated (FTO) protein on macrophage polarization and its subsequent effects on diabetic microvasculopathy. We found that diabetes induces a shift in macrophage polarization toward a proinflammatory M1 phenotype, which is associated with a reduction in m6A modification levels. Notably, FTO emerges as a critical regulator of m6A under diabetic conditions. In vitro experiments reveal that FTO not only modulates macrophage polarization but also mediates their interactions with vascular endothelial cells. In vivo experiments demonstrate that FTO deficiency exacerbates retinal inflammation and microvascular dysfunction in diabetic retinas. Mechanistically, FTO stabilizes mRNA through an m6A-YTHDF2–dependent pathway, thereby activating the PI3K/AKT signaling cascade. Collectively, these findings position FTO as a promising therapeutic target for the management of diabetic vascular complications. Article Highlights:

Neurovascular dysfunction is a preclinical manifestation of diabetic complications, including diabetic retinopathy (DR). Herein, we report that a transfer RNA-derived RNA fragment, tRF-3001a, is significantly upregulated under diabetic conditions. tRF-3001a downregulation inhibits Müller cell activation, suppresses endothelial angiogenic effects, and protects against high-glucose-induced retinal ganglion cell injury in vitro. Furthermore, tRF-3001a downregulation alleviates retinal vascular dysfunction, inhibits retinal reactive gliosis, facilitates retinal ganglion cell survival, and preserves visual function and visually guided behaviors in STZ-induced diabetic mice and db/db diabetic mice. Mechanistically, tRF-3001a regulates neurovascular dysfunction in a microRNA-like mechanism by targeting GSK3B. Clinically, tRF-3001a is upregulated in aqueous humor (AH) samples of DR patients. tRF-3001a downregulation inhibits DR-induced human retinal vascular endothelial cell and Müller cell dysfunction in vitro and DR-induced retinal neurovascular dysfunction in C57BL/6J mice. Thus, targeting tRF-3001a-mediated signaling is a promising strategy for the concurrent treatment of vasculopathy and neuropathy in diabetes mellitus.