Endothelial dysfunction in vascular complications of diabetes: a comprehensive review of mechanisms and implications

Abstract

Diabetic vascular complications are prevalent and severe among diabetic patients, profoundly affecting both their quality of life and long-term prospects. These complications can be classified into macrovascular and microvascular complications. Under the impact of risk factors such as elevated blood glucose, blood pressure, and cholesterol lipids, the vascular endothelium undergoes endothelial dysfunction, characterized by increased inflammation and oxidative stress, decreased NO biosynthesis, endothelial-mesenchymal transition, senescence, and even cell death. These processes will ultimately lead to macrovascular and microvascular diseases, with macrovascular diseases mainly characterized by atherosclerosis (AS) and microvascular diseases mainly characterized by thickening of the basement membrane. It further indicates a primary contributor to the elevated morbidity and mortality observed in individuals with diabetes. In this review, we will delve into the intricate mechanisms that drive endothelial dysfunction during diabetes progression and its associated vascular complications. Furthermore, we will outline various pharmacotherapies targeting diabetic endothelial dysfunction in the hope of accelerating effective therapeutic drug discovery for early control of diabetes and its vascular complications.

Keywords: atherosclerotic; diabetes; endothelial dysfunction; therapies; vascular diseases.

Figure 1

A schematic overview of diabetic vascular complications. Diabetic vascular complications include macrovascular complications (diabetic coronary artery disease, cerebrovascular disease, and peripheral vascular disease) and microvascular complications (diabetic retinopathy, nephropathy, cardiomyopathy, and neuropathy). Continued exposure to risk factors causes endothelial dysfunction, leading to lipid retention in the endothelium. Monocytes differentiate into macrophages, internalize modified lipoproteins, and form foam cells. Activated foam cells induce inflammation by secreting cytokines through several downstream signals. In addition, endothelial cells undergo EndMT, cell death, etc., further exacerbating the atherosclerotic process.

Figure 2

The bibliometric data obtained using VOSviewer. It shows the frequency of keywords in the literature related to diabetes and its vascular complications. The color of dots and lines represent the average year of publication for the corresponding term.

Figure 3

Molecular mechanisms of diabetic endothelial dysfunction. The mechanisms of diabetic endothelial dysfunction are complicated and include oxidative stress, inflammation, EndMT, and cell death. Most of these related factors work together to accelerate the process of diabetic endothelial dysfunction through different signaling pathways, which ultimately lead to diabetic vascular complications.

Figure 4

Molecular mechanisms of diabetic macrovascular complications. Hyperglycemia leads to endothelial dysfunction, atherosclerosis (AS), and diabetic macrovascular disorders, including coronary artery disease (CAD), cerebrovascular disease, and peripheral vascular disease. These conditions affect each other in a vicious cycle if they are not treated appropriately.

Figure 5

Molecular mechanisms of diabetic microvascular complications. In diabetic endothelial dysfunction, individuals are susceptible to microvascular complications such as diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, and diabetic cardiomyopathy. The development of these complications is due to some common factors such as increased inflammation, ROS, EndMT, and endothelial cell death. For diabetic neuropathy, the upregulation of NOX2, NOX4, and VEGFA and the downregulation of Dhh can enhance its progression. Diabetic nephropathy can be accelerated by the upregulation of LRG1, GRP56, RIPK1, RIPK3, and TGF-β/ALK1 and the downregulation of ABCA1 and cAMP/PKA. In diabetic retinopathy, the exacerbations of ET-1, HIF-1α, FBXW7, and Hcy can worsen the condition. For diabetic cardiomyopathy, higher expression of GLU-1, MICU1, and iNOS contributes to its development.