Diabetes significantly elevates the susceptibility to various cardiovascular disorders, encompassing macrovascular complications leading to coronary heart disease and cardiomyopathy, as well as microvascular diseases like diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy [1,2]. Notably, vascular complications in diabetes are identified as primary instigators of cardiovascular diseases [3]. The endothelial layer lining the vasculature forms a semi-permeable selective barrier that governs macromolecular and fluid exchange between the bloodstream and interstitial tissue. Endothelial cell dysfunction (ECD) emerges as a pivotal factor in the genesis of these diabetic complications, manifesting in compromised vasodilation and impaired endothelial cell barrier function [4,5]. The functional integrity of the endothelial barrier is contingent upon the dynamic architecture of endothelial cell–cell junctions, including tight junctions (TJ), adherens junctions (AJ), and a spectrum of adhesion molecules. TJs comprise homophilic cell-cell adhesion molecules such as occludin, claudin, and functional adhesion molecules like junctional adhesion molecules (JAMs). AJs encompass the vascular endothelial (VE)-cadherin complex and catenin. VE-cadherin possesses a modular structure, featuring five extracellular repeats, a transmembrane domain, and a cytoplasmic tail. The extracellular domain of VE-cadherin facilitates homophilic interactions, while the cytoplasmic tail binds to intracellular partners like β- and p120-catenins, vinculin, α-actinin, and plakoglobin [6,7]. The preservation of vascular endothelium integrity is critical for sustaining the structural and functional equilibrium of the vascular system [8]. Extensive evidence underscores that both hyperglycemia and hyperlipidemia significantly augment reactive oxygen species (ROS) generation [9,10]. The resultant surplus of ROS exacerbates endothelial permeability [11,12]. Thus, the identification of novel therapeutic targets for diabetes aimed at safeguarding endothelial cells holds immense promise.

Hydrogen sulfide (H2S), an endogenous gaseous molecule, has demonstrated significant therapeutic potential in various cardiovascular diseases, including anti-hypertensive effects, mitigation of cardiac ischemia-reperfusion injury, and attenuation of atherosclerosis [[13], [14], [15]]. H2S generation in mammalian tissues involves three key enzymes: cystathionine-β-synthetase (CBS), cystathionine-γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST) [16]. Among these, CSE predominantly mediates H2S production in endothelial cells [17]. H2S exerts its effects through the modification of cysteine residues in proteins, a process known as protein sulfhydration, which in turn regulates protein structure and activity [18,19]. Notably, H2S plays a crucial role in maintaining endothelial homeostasis, and its deficient endogenous production is linked to the pathogenesis of endothelial dysfunction [20]. Functionally, H2S has been shown to effectively impede vascular calcification [21], hinder macrophage foam cell formation [22], reduce monocyte adhesion resulting from endothelial cell (EC) activation [23], and promote vascular relaxation [24]. Additionally, in diabetic mice, H2S has been observed to restore nitric oxide efficacy, reduce oxidative stress in the mouse aorta, and consequently enhance endothelial function [25]. However, limited evidence exists regarding the association between H2S and endothelial barrier function. Thus, in this present study, we postulate that H2S may exert a protective effect on endothelial cells by modulating endothelial barrier function.