Epigenetic Changes in Endothelial Progenitors as a Possible Cellular Basis for Glycemic Memory in Diabetic Vascular Complications

Abstract

The vascular complications of diabetes significantly impact the quality of life and mortality in diabetic patients. Extensive evidence from various human clinical trials has clearly established that a period of poor glycemic control early in the disease process carries negative consequences, such as an increase in the development and progression of vascular complications that becomes evident many years later. Importantly, intensive glycemic control established later in the disease process cannot reverse or slow down the onset or progression of diabetic vasculopathy. This has been named the glycemic memory phenomenon. Scientists have successfully modelled glycemic memory using various in vitro and in vivo systems. This review emphasizes that oxidative stress and accumulation of advanced glycation end products are key factors driving glycemic memory in endothelial cells. Furthermore, various epigenetic marks have been proposed to closely associate with vascular glycemic memory. In addition, we comment on the importance of endothelial progenitors and their role as endogenous vasoreparative cells that are negatively impacted by the diabetic milieu and may constitute a “carrier” of glycemic memory. Considering the potential of endothelial progenitor-based cytotherapies, future studies on their glycemic memory are warranted to develop epigenetics-based therapeutics targeting diabetic vascular complications.

Effect of Vildagliptin, Compared to Sitagliptin, on the Onset of Hyperglycemia-Induced Metabolic Memory in Human Umbilical Vein Endothelial Cells

“…Occurrence of this phenomenon has been reported in endothelial cells, in which it is driven by different mechanisms, such as oxidative stress and epigenetic changes [19]. DDP-4 inhibitors are anti-diabetic agents with vascular protective effects [32].…”

“…It has also been shown that following a hyperglycemic stress, the levels of basement membrane proteins such as collagen and fibronectin, which are markers of high glucose stress, remain elevated several days after glucose levels have normalized [16,17]. This phenomenon, defined as "metabolic memory", has been linked to poor glycemic control in the early phases of diabetes, despite a tight glycemic control achieved during the course of the disease [18][19][20]. Several preclinical and clinical studies have demonstrated the existence of a metabolic memory in endothelial cells [19].…”

“…This phenomenon, defined as "metabolic memory", has been linked to poor glycemic control in the early phases of diabetes, despite a tight glycemic control achieved during the course of the disease [18][19][20]. Several preclinical and clinical studies have demonstrated the existence of a metabolic memory in endothelial cells [19]. Moreover, it has been shown that normalization of the extracellular glucose level does not switch off the intracellular pro-oxidant environment, suggesting a role for ROS in the onset of cellular memory [16].…”

Vasculogenesis and Its Cellular Therapeutic Applications

“…The 'early' outgrowth cells, selected by short-term culture, are classified as immediately adherent cells of hematopoietic origin expressing CD45, CD14 and CD11b, apart from VEGFR2 (Flk-1). They are able to support vasculogenesis and angiogenesis but are not able to spontaneously form tubules in vitro [Rehman et al, 2003;Hirschi et al, 2008;Yoder, 2012Yoder, , 2013Rajasekar et al, 2015;Recchioni et al, 2016]. The 'early' EPCs contribute to angiogenesis in a paracrine manner by secreting proangiogenic molecules, and are able to incorporate into capillaries in perivascular positions [Hirschi et al, 2008].…”

Epigenetic Mechanisms of Endothelial Progenitor Cell Dysfunction

“…Importantly, the deregulation of epigenetic features of EPCs plays a key role in DM-induced vascular injury and endothelial dysfunction [11]. DNA methylation / hydroxymethylation / transmethylation, histone modifications, and differential expression of specific non-coding RNAs like microRNA (miRNAs) are discussed as causative mechanisms of epigenetic modifications [12]. Despite this, the early phases of epigenetically changes in EPCs are pre-diabetic situation affected mitochondrial injury upon hyperglycemic insult, oxidative stress activation, and lowering survival ability of cell organelles [13].…”