Senescent endothelial cells: a potential target for diabetic retinopathy

Abstract

Diabetic retinopathy (DR) is a diabetic complication that results in visual impairment and relevant retinal diseases. Current therapeutic strategies on DR primarily focus on antiangiogenic therapies, which particularly target vascular endothelial growth factor and its related signaling transduction. However, these therapies still have limitations due to the intricate pathogenesis of DR. Emerging studies have shown that premature senescence of endothelial cells (ECs) in a hyperglycemic environment is involved in the disease process of DR and plays multiple roles at different stages. Moreover, these surprising discoveries have driven the development of senotherapeutics and strategies targeting senescent endothelial cells (SECs), which present challenging but promising prospects in DR treatment. In this review, we focus on the inducers and mechanisms of EC senescence in the pathogenesis of DR and summarize the current research advances in the development of senotherapeutics and strategies that target SECs for DR treatment. Herein, we highlight the role played by key factors at different stages of EC senescence, which will be critical for facilitating the development of future innovative treatment strategies that target the different stages of senescence in DR.

Keywords: Cellular senescence; Diabetic retinopathy; Endothelial cells; Pathological vascular remodeling; Senotherapeutics.

Fig. 1

Key factors inducing endothelial cell senescence in diabetic retinopathy. The figure above illustrates a series of mechanisms through which hyperglycemia induces endothelial cell senescence. Among these, increased inflammation, increased ROS and decreased NO are the focus of this section’s discussion, and these changes are also simultaneously reflected in the endothelial SASP. This confirms the relevance and reasonability of the occurrence, maintenance, and spread of EC senescence under hyperglycemic conditions. DDR, DNA damage response; SASP, senescence-associated secretory phenotype; NO, nitric oxide; ROS, reactive oxygen species; AGEs, advanced glycation end products. This figure was created using Figdraw

Fig. 2

Dual effects of endothelial cell senescence in diabetic retinopathy. Endothelial cell senescence plays a dual role in different stages of diabetic retinopathy. The harmful aspects are characterized by the induction of microvascular rarefaction during NPDR and pathological angiogenesis during PDR; the beneficial aspects are manifested by vascular remodeling in the later stage of pathological angiogenesis, which is a self-correcting process, including the regression of pathological angiogenesis and regeneration of functional vessels. This effect switch is closely related to the shift in components of the endothelial SASP in a highly context-dependent manner. SECs, senescent endothelial cells; SASP, senescence-associated secretory phenotype; iBRB, internal blood–retinal barrier; BM, basement membrane; NETs, neutrophil extracellular traps; IL-8, interleukin-8; IL-1β, interleukin-1β; CXCL1, C-X-C motif chemokine ligand 1. This figure was created using Figdraw