Endothelial dysfunction: molecular mechanisms and clinical implications

Abstract

Cardiovascular disease (CVD) and its complications are a leading cause of death worldwide. Endothelial dysfunction plays a crucial role in the initiation and progression of CVD, serving as a pivotal factor in the pathogenesis of cardiovascular, metabolic, and other related diseases. The regulation of endothelial dysfunction is influenced by various risk factors and intricate signaling pathways, which vary depending on the specific disease context. Despite numerous research efforts aimed at elucidating the mechanisms underlying endothelial dysfunction, the precise molecular pathways involved remain incompletely understood. This review elucidates recent research findings on the pathophysiological mechanisms involved in endothelial dysfunction, including nitric oxide availability, oxidative stress, and inflammation-mediated pathways. We also discuss the impact of endothelial dysfunction on various pathological conditions, including atherosclerosis, heart failure, diabetes, hypertension, chronic kidney disease, and neurodegenerative diseases. Furthermore, we summarize the traditional and novel potential biomarkers of endothelial dysfunction as well as pharmacological and nonpharmacological therapeutic strategies for endothelial protection and treatment for CVD and related complications. Consequently, this review is to improve understanding of emerging biomarkers and therapeutic approaches aimed at reducing the risk of developing CVD and associated complications, as well as mitigating endothelial dysfunction.

Keywords: cardiovascular disease; endothelial dysfunction; inflammation; nitric oxide; oxidative stress.

FIGURE 1

The generation of NO by eNOS coupling. By binding to the CaM, electrons are transferred through the FMN and FAD domains. In the presence of heme and BH4, NOS monomers form homodimers capable of catalyzing the transformation of l‐arginine and O₂ into l‐citrulline and NO. Abbreviations: CaM, calcium signaling protein calmodulin; FMN, flavin adenine mononucleotide; FAD, flavin adenine dinucleotide.

FIGURE 2

The NO signaling in VSMC. NO diffuses into adjacent VSMC and activates sGC, converting GTP to cGMP, which can be degraded by PDE5 to the inactive 5'‐GMP. cGMP causes vasodilation through PKG. Abbreviations: sGC, soluble guanylate cyclase; GTP, guanosine triphosphate; cGMP, cyclic guanosine monophosphate; PDE5, phosphodiesterase type 5; PKG, cGMP‐dependent protein kinase.

FIGURE 3

EC exhibits proinflammatory and proatherosclerotic phenotypes upon inflammation and atherosclerosis conditions. cLDL, carbamylated low‐density lipoprotein; ATF, activating transcription factor; CREB, cyclic adenosine monophosphate response element‐binding protein; eNOS, endothelial nitric oxide synthase; ER, endoplasmic reticulum; ICAM1, intercellular adhesion molecule 1; LOX‐1, lectin‐type oxidized low‐density lipoprotein receptor 1; NADPH, nicotinamide adenine dinucleotide phosphate; NET, neutrophil extracellular trap; NO, nitric oxide; NF‐κB, nuclear factor kappa‐light‐chain enhancer of activated B cells; oxHDL, oxidized high‐density lipoprotein; oxLDL, oxidized low‐density lipoprotein; TLR2, toll‐like receptor 2; VCAM‐1, vascular cell adhesion molecule 1; SDMA, symmetric dimethylarginine; ZO‐1, zonula occludens‐1.

FIGURE 4

CVD and its complications are caused by endothelial dysfunction. Many disease conditions are caused by endothelial dysfunction due to imbalances in vasodilators and vasoconstrictors. Several major diseases such as atherosclerosis, diabetes, hypertension, stroke, peripheral arterial disease, CKD, and metabolic syndrome are associated with endothelial dysfunction.

FIGURE 5

Endothelial dysfunction is caused by many factors and can be improved by several therapeutic strategies.