Retinal Endothelial Cell Apoptosis Stimulates Recruitment of Endothelial Progenitor Cells

Abstract

Purpose Bone marrow–derived endothelial progenitor cells (EPCs) contribute to vascular repair although it is uncertain how local endothelial cell apoptosis influences their reparative function. This study was conducted to determine how the presence of apoptotic bodies at sites of endothelial damage may influence participation of EPCs in retinal microvascular repair. Methods Microlesions of apoptotic cell death were created in monolayers of retinal microvascular endothelial cells (RMECs) by using the photodynamic drug verteporfin. The adhesion of early-EPCs to these lesions was studied before detachment of the apoptotic cells or after their removal from the wound site. Apoptotic bodies were fed to normal RMECs and mRNA levels for adhesion molecules were analyzed. Results Endothelial lesions where apoptotic bodies were left attached at the wound site showed a fivefold enhancement in EPC recruitment (P < 0.05) compared with lesions where the apoptotic cells had been removed. In intact RMEC monolayers exposed to apoptotic bodies, expression of ICAM, VCAM, and E-selectin was upregulated by 5- to 15-fold (P < 0.05– 0.001). EPCs showed a characteristic chemotactic response (P < 0.05) to conditioned medium obtained from apoptotic bodies, whereas analysis of the medium showed significantly increased levels of VEGF, IL-8, IL-6, and TNF-α when compared to control medium; SDF-1 remained unchanged. Conclusions The data indicate that apoptotic bodies derived from retinal capillary endothelium mediate release of proangiogenic cytokines and chemokines and induce adhesion molecule expression in a manner that facilitates EPC recruitment.

The Matricellular Protein Cysteine-rich Protein 61 (CCN1/Cyr61) Enhances Physiological Adaptation of Retinal Vessels and Reduces Pathological Neovascularization Associated with Ischemic Retinopathy

“…TNF receptor-deficient mice exhibit a prolonged neovascular response in the model of OIR (59), with an associated decrease in endothelial cell apoptosis in the neovascular tufts. Other studies showed that apoptotic bodies derived from neovessel mediate release of cytokines and chemokines that facilitate progenitor cell recruitment, further supporting a role for TNF-␣ in vascular tuft regression (60). Additionally, CCN1 enhances the apoptotic activity of TRAIL and Fas ligand, which has been shown to be involved in endothelial cell death associated with vascular tuft regression (61).…”

Differential Modulation of Circulating Endothelial Progenitor Cells in Peripheral Blood Monocyte Population of an Early Stage of Streptozotocin-Induced Diabetic Retinopathy

“…In response to signal from injured endothelial cells and retinal ischemia, EPCs were recruited, mobilized and home to ischemic areas in order to assist vascular remodeling and thereby maintaining normal vasculature. 5,6 Recent evidences support the notion that type 1 and type 2 diabetic patients have diverse number of circulating EPCs. 7,8 Increasing evidence suggests that circulating EPCs contribute to pathological neo-vascularization in diabetes induced retinal stress.…”

The retinal clock in mammals: role in health and disease

“…Per2-knockout mice exhibit retinal vascular damage, reduction in retinal thickness, and a decrease in the electroretinogram (ERG) amplitude, similar to those found in type 2 diabetes. [13][14][15] A double-clock gene mutant, the Per1…”

“…92 Clock mutant and Bmal1 conditional knockout mice develop type 1 diabetes, 93 whereas Per2-knockout mice exhibit retinal phenotype similar to that found in type 2 diabetes. [13][14][15] Conversely, diabetes is also associated with circadian disruption of clock gene expression. In rodent models of type 1 94,96 or type 2 95 diabetes, the expression of several clock genes, including Clock, Bmal1, Per1-Per2, and Cry1-2, was downregulated in the retina, whereas no alterations were observed in the SCN.…”