Angiogenic microenvironment augments impaired endothelial responses under diabetic conditions

Abstract

Diabetes-induced cardiomyopathy is characterized by cardiac remodeling, fibrosis, and endothelial dysfunction, with no treatment options currently available. Hyperglycemic memory by endothelial cells may play the key role in microvascular complications in diabetes, providing a potential target for therapeutic approaches. This study tested the hypothesis that a proangiogenic environment can augment diabetes-induced deficiencies in endothelial cell angiogenic and biomechanical responses. Endothelial responses were quantified for two models of diabetic conditions: 1) an in vitro acute and chronic hyperglycemia where normal cardiac endothelial cells were exposed to high-glucose media, and 2) an in vivo chronic diabetes model where the cells were isolated from rats with type I streptozotocin-induced diabetes. Capillary morphogenesis, VEGF and nitric oxide expression, cell morphology, orientation, proliferation, and apoptosis were determined for cells cultured on Matrigel or proangiogenic nanofiber hydrogel. The effects of biomechanical stimulation were assessed following cell exposure to uniaxial strain. The results demonstrate that diabetes alters cardiac endothelium angiogenic response, with differential effects of acute and chronic exposure to high-glucose conditions, consistent with the concept that endothelial cells may have a long-term “hyperglycemic memory” of the physiological environment in the body. Furthermore, endothelial cell exposure to strain significantly diminishes their angiogenic potential following strain application. Both diabetes and strain-associated deficiencies can be augmented in the proangiogenic nanofiber microenvironment. These findings may contribute to the development of novel approaches to reverse hyperglycemic memory of endothelium and enhance vascularization of the diabetic heart, where improved angiogenic and biomechanical responses can be the key factor to successful therapy.

Neuregulin-1 Promotes Myocardial Angiogenesis in the Rat Model of Diabetic Cardiomyopathy

“…These results are consistent with the findings of previous studies [3-6]. Cardiac remodeling induced by diabetes is associated with microvascular pathologies, which include reduced expression of angiogenic factors, decreased endothelial cell infiltration, increased endothelial cell apoptosis [24], decreased circulating endothelial precursor cells (EPCs) and impaired EPCs function [25, 26]. …”

lncRNA-MIAT Regulates Microvascular Dysfunction by Functioning as a Competing Endogenous RNA

“…23,25 We thus selected an endothelial cell line to study the mechanistic aspects and functional significance of MIAT alteration in vitro. MIAT small interfering RNA transfection caused a marked reduction in the level of MIAT but not other lncRNAs.…”

TGR5 receptor activation attenuates diabetic retinopathy through suppression of RhoA/ROCK signaling

“…Inflammatory factors such as TNF-α play important roles in the development of diabetic vascular complications. 23 Thus we selected TNF-α for the follow-up investigation to identify the effect of INT-777 on endothelial cells. CCK-8 assay ( Figure 4A) and Ki67 staining ( Figure 4B) were used to monitor cell proliferation.…”