Stick to the Script: How Endomucin Keeps the Glycocalyx in Line

Endothelial dysfunction commonly accompanies declines in vascular and renal function (1), significantly contributing to increased cardiovascular morbidity and mortality (2). For instance, individuals with end-stage kidney disease face mortality rates up to 1000 times higher than those of similar-aged peers with healthy kidney function (3). Thus, there is an urgent need to understand the mechanisms driving endothelial dysfunction. Among the emerging areas of interest is the endothelial glycocalyx, a critical structure composed of glycoproteins and proteoglycans lining the apical surface of endothelial cells. Functionally, the glycocalyx protects the endothelial membrane, limits molecular access, and dissipates fluid shear stress (4).

Previous research, including studies from our group and others, has demonstrated that dietary sodium contributes to endothelial dysfunction and profoundly impacts the glycocalyx (5, 6). High sodium intake is known to disrupt glycocalyx structure and function, potentially through electrostatic interactions leading to endothelial stiffening, impaired nitric oxide bioavailability, and increased leukocyte adhesion (7). Our studies indicate that sodium-induced glycocalyx damage is associated with salt sensitivity of blood pressure in women but not men (8) especially in people living with HIV (9). While these insights highlight sodium as a major contributor to glycocalyx damage, they also raise a critical question: What intrinsic factors maintain glycocalyx integrity, and how do their dysfunctions contribute to endothelial and renal damage?

In this issue of Circulation Research, Hu et al. shed light on endomucin (EMCN) and its pivotal role in maintaining endothelial and renal health (10). EMCN has been recently identified as having anti-adhesive properties (11), and that its expression in endothelial cells promotes cell detachment and interferes with the assembly of focal adhesion complexes (12), and leukocyte adhesion (13). Moreover, endothelial cell-specific knockout of EMCN in mice disrupted signaling pathways that maintain tight junctions between endothelial cells, leading to compromised barrier function (14). Utilizing a global EMCN knockout (KO) mouse model, Hu et al. challenge the long-held assumption that global EMCN KO would be embryonically lethal. Their findings offer profound insights into how EMCN deficiency disrupts endothelial function and contributes to kidney damage where its expression is highest relative to other organs. They utilized a multifaceted strategy to develop a deeper and more nuanced understanding of the mechanisms by which EMCN loss disrupts glomerular function. Histological analysis revealed that KO mice glomeruli were smaller with higher collagen deposition. EMCN KO mice exhibited increased leukocyte infiltration in the glomeruli, accompanied by upregulation of vascular cell adhesion molecule-1 (VCAM-1). They also performed urinalysis and observed glomerular dysfunction and albuminuria. These findings align with EMCN’s known anti-adhesive properties, emphasizing its role in suppressing leukocyte-endothelial interactions and preserving glomerular function, under physiological conditions. Loss of EMCN also disrupted glomerular endothelial tight junctions, leading to albuminuria, a hallmark of glomerular filtration barrier (GFB) dysfunction. Notably, these effects were independent of blood pressure changes. Transmission electron microscopy revealed significant structural alterations in EMCN KO glomeruli, including thickened endothelial cells, disorganized fenestrations, and fused podocyte foot processes. Transcriptional analysis further identified dysregulation of genes associated with endothelial cell junctions, glycocalyx structure, and podocyte function.

In conclusion, Hu et al.’s findings build upon the broader understanding of the glycocalyx as a dynamic regulator of endothelial health. Importantly, their work highlights EMCN’s role in maintaining the delicate crosstalk between endothelial cells and podocytes, which is essential for GFB function. This research opens new avenues for investigating glycocalyx-associated proteins as potential therapeutic targets. EMCN may represent a protective factor whose function is compromised by external insults like high sodium intake. Future studies should aim to integrate these perspectives, exploring how EMCN and other glycocalyx components modulate vascular responses to dietary and environmental stressors. Their findings not only enhance our understanding of EMCN’s role in glomerular physiology but also reinforce the glycocalyx’s significance as a central regulator of vascular health. As we continue to investigate the complex interactions between glycocalyx components, endothelial cells, and external stressors, EMCN emerges as a promising target for addressing the pathophysiology of endothelial dysfunction and related diseases. These results build upon previous findings, which are illustrated in Figure 1, highlighting the multifaceted role of EMCN.

Figure 1. The multifacited role of endomucin.

The Figure summarizes information collected from the literature and depicts the impact of normal versus knockout endomucin expression. In the wild-type mice, the inflammatory response is reduced by increasing the antiadhesive properties of the glycocalyx, in the knockout mice, this is reduced which promotes increased adhesion and infiltration of immune cells. Renal function is impaired in the knockout due to podocyte dysfunction. Cell interactions are disrupted in the knockout mice due to endothelial cell membrane remodeling. Cell morphology is altered in the knockout mice resulting in increased membrane permeability and protein leakage.