Increase in acid sphingomyelinase level in human retinal endothelial cells and CD34+ circulating angiogenic cells isolated from diabetic individuals is associated with dysfunctional retinal vasculature and vascular repair process in diabetes

Abstract

Background Diabetic retinopathy (DR) is a microvascular disease that results from retinal vascular degeneration and defective repair due to diabetes induced endothelial progenitor dysfunction. Objective Understanding key molecular factors involved in vascular degeneration and repair is paramount for developing effective DR treatment strategies. We propose that diabetes-induced activation of acid sphingomyelinase (ASM) plays essential role in retinal endothelial and CD34+ circulating angiogenic cell (CAC) dysfunction in diabetes. Methods Human retinal endothelial cells (HRECs) isolated from control and diabetic donor tissue and human CD34+ CACs from control and diabetic patients were used in this study. ASM mRNA and protein expression was assessed by quantitative PCR and ELISA, respectively. To evaluate the effect of diabetes-induced ASM on HRECs and CD34+ CACs function, tube formation, CAC incorporation into endothelial tubes, and diurnal release of CD34+ CACs in diabetic individuals was determined. Results ASM expression level was significantly increased in HRECs isolated from diabetic compared to control donor tissue, as well as CD34+CACs and plasma of diabetic patients. A significant decrease in tube area was observed in HRECs from diabetic donors as compared to control HRECs. The tube formation deficiency was associated with increased expression of ASM in diabetic HRECs. Moreover, diabetic CD34+ CACs with high ASM showed defective incorporation into endothelial tubes. Diurnal release of CD34+ CACs was disrupted with the rhythmicity lost in diabetic patients. Conclusion Collectively, these findings support that diabetes-induced ASM upregulation has a marked detrimental effect on both retinal endothelial cells and CACs.

High glucose and free fatty acids induce endothelial progenitor cell senescence via PGC‐1α/SIRT1 signaling pathway

“…It has been well documented that increased prevalence of macrovascular and microvascular complications in type 2 diabetes mellitus (T2DM) is closely associated with impaired function of endothelial as well as endothelial progenitor cells (Fadini et al, 2005;Chen et al, 2009;Saboor et al, 2014;Yiu and Tse 2014;Kady et al, 2017). Endothelial progenitor cells (EPCs), recruited from the bone marrow and circulating in the peripheral blood, have the capability to differentiate into endothelial cells and seem to play a pivotal role for the repair of endothelium and to improve neovascularization (Schmidt-Lucke et al, 2005;Westerweel et al, 2013;Abplanalp et al, 2016).…”

Circulating angiogenic stem cells in type 2 diabetes are associated with glycemic control and endothelial dysfunction

“…Additional causality and mechanistic studies are needed to more clearly define the relationship between CACs and diabetes in humans. Nevertheless, indications from prior human and animal studies are consistent with the idea that attenuated vascular repair due to low levels of pro-angiogenic cells, or dysfunctional pro-angiogenic cells promotes endothelial dysfunction and pathological outcomes such as retinopathy [ 29 ], neuropathy [ 11 , 35 ], and nephropathy [ 10 , 36 ].…”

“…Several prior animal [ 25 , 28 , 33 ] and human [ 24 , 26 , 27 , 29 ] studies have demonstrated an inverse relationship between CAC levels and incidence of diabetes. However, as these studies pre-selected the diabetic phenotype and used variable markers to identify CACs, it remains unclear which cell phenotype is most predictive of diabetes.…”

“…Hence, a reduced level of these cells in diabetes is indicative of poor vascular repair capacity and their measurement may be useful as a clinical marker of disease progression. Similarly, acid sphingomyelinase (ASM) activation in CD34 + reparative cells of diabetics is associated with their impaired functionality [ 29 ] and measurements of ASM activity can likewise be used to predict vascular repair capacity and vascular health in diabetics.…”

Restoring Vision by Regenerative Medicine Using Stem Cell: A Review

“…DR depends on the entire retinal cell. The experimental manifestation of RD primarily owes to change in the retina [44]. Vision loss is mostly due to retinal dysfunction.…”