Pericyte Bridges in Homeostasis and Hyperglycemia: Reconsidering Pericyte Dropout and Microvascular Structures

Abstract

Diabetic retinopathy threatens the vision of a third of diabetic patients. Progression of the disease is attributed to the dropout of pericytes, a cell type that enwraps and stabilizes the microvasculature. In tandem with this presumptive pericyte dropout, there is enriched formation of structures assumed to be remnants of collapsed or regressed vessels, previously classified as acellular capillaries, string vessels, and basement membrane bridges. Instead of endothelial cells, we show that pericytes colocalize with basement membrane bridges, and both bridging structures are enriched by cell-specific knockout of KLF4 and reversibly enriched with elevation of Ang-2, PDGF-BB, and blood sugar. Our data suggests that pericyte counts from retinal digests have misclassified pericyte bridges as endothelial structures and have exaggerated the role of pericyte loss in DR progression. In vivo imaging of corneal limbal vessels demonstrates pericyte migration off-vessel, implicating pericyte movement in formation of pericyte bridges and pathogenesis of diabetic retinopathy.

Metabolic Coordination of Pericyte Phenotypes: Therapeutic Implications

“…This suggests that increased conversion of glycolytic intermediary glyceraldehyde 3 phosphate to AGEs can influence a transcription factor that itself is a cornerstone in the regulation of cell survival, metabolism and proliferation/differentiation. Within the retina, prolonged hyperglycemia ultimately is associated with pericyte migration away from the capillary or pericyte 'dropout, ' which decreases pericyte coverage of the capillary structure, compromising capillary integrity and provoking capillary regression (Pfister et al, 2008;Corliss et al, 2019;Hayes, 2019).…”

Expression and significance of Ang-2/Ang-1 in the vitreous of patients with proliferative diabetic retinopathy

“…PDR is the most serious complication of DR, and 50% of untreated PDR patients develop irreversible blindness within 5 years of diagnosis [2] . Multiple mechanisms contribute to vision loss in DR, including metabolic changes [3,4] , coagulation and hemodynamic disorders [5,6] , hypoxia and oxidative stress [7,8] , and microvascular activation due to a variety of proangiogenic cytokines [9] . Accumulating evidence has revealed several angiogenic factors that may contribute to the progression of DR, such as vascular endothelial growth factor [4,10] , basic broblast growth factor [11,12] , insulin-like growth factor [13] , tumor necrosis factor-α [14] , interleukin-1ß [15] , angiopoietin [16] , hepatocyte growth factor [17] , monocyte chemoattractant protein-1 [18] and platelet-derived growth factor [19] , the expression of which have been detected in the vitreous of PDR patients.…”