Understanding Diabetic Vascular Dysfunction

Diabetes mellitus is a chronic metabolic disorder that, over time, leads to profound damage in the vascular system. This damage, known as diabetic vascular dysfunction, is the root cause of many of the most devastating complications of diabetes, including coronary artery disease, stroke, peripheral arterial disease, and nephropathy. The underlying mechanisms are complex, involving hyperglycemia-induced oxidative stress, advanced glycation end-products (AGEs), chronic low-grade inflammation, and endothelial cell dysfunction. Early identification of individuals at high risk for these complications is essential for timely intervention. Biomarkers that reflect the health of the endothelium are therefore of great clinical interest. One such biomarker that has garnered significant attention is serum endoglin, also known as CD105.

Endoglin is a transmembrane glycoprotein predominantly expressed on endothelial cells, but it is also found on activated monocytes, macrophages, and certain stem cells. Its primary function is to modulate signaling by members of the transforming growth factor-β (TGF-β) superfamily. By binding TGF-β ligands, endoglin influences downstream Smad signaling pathways that control cell proliferation, migration, and differentiation. In the vasculature, this translates into a critical role in angiogenesis — the formation of new blood vessels from pre-existing ones. However, when vascular endothelium is stressed, as occurs in diabetes, endoglin expression and its shed soluble form — serum endoglin — can become dysregulated.

The Biology of Endoglin and Its Soluble Form

Structure and Function of Membrane-Bound Endoglin

Endoglin exists in two major isoforms: long (L-endoglin) and short (S-endoglin), with the long form being the predominant one in endothelial cells. It is a co-receptor for several TGF-β family ligands, including TGF-β1, TGF-β3, activin-A, and bone morphogenetic proteins (BMPs). The binding of these ligands to their type I and type II receptors, in concert with endoglin, activates intracellular signaling cascades. In endothelial cells, endoglin promotes ALK1-mediated signaling (activin receptor-like kinase 1) over ALK5-mediated signaling, which favors a pro-angiogenic, proliferative phenotype. This delicate balance is essential for maintaining vascular integrity and for normal vascular repair.

Shedding and Generation of Serum Endoglin

The extracellular domain of endoglin can be cleaved by matrix metalloproteinase-14 (MMP-14, also known as MT1-MMP), releasing a soluble fragment into the circulation. This soluble endoglin (sEng) is what is measured as "serum endoglin" in clinical studies. Importantly, sEng is not merely an inert breakdown product; it retains the ability to bind TGF-β ligands and can function as a decoy receptor, thereby modulating TGF-β signaling in distant cells. High levels of sEng have been implicated in pathological conditions, including preeclampsia, cardiovascular disease, and diabetic complications. The enzymatic cleavage process may be upregulated in a pro-inflammatory environment, linking vascular inflammation directly to elevated sEng levels.

Serum Endoglin in Diabetic Vascular Dysfunction: Evidence from Studies

Elevated Levels in Diabetic Patients

Numerous cross-sectional and cohort studies have consistently demonstrated that serum endoglin levels are significantly higher in individuals with type 1 and type 2 diabetes compared to healthy controls. For example, a meta-analysis of 14 studies found that diabetic patients had a standardized mean difference in sEng levels of 1.24 (95% CI: 0.78–1.70) relative to non-diabetic subjects. Furthermore, sEng correlates positively with glycated hemoglobin (HbA1c), fasting blood glucose, and duration of diabetes, suggesting a direct relationship between glycemic burden and endothelial stress. Elevated sEng is also associated with markers of endothelial dysfunction, such as soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble intercellular adhesion molecule-1 (sICAM-1).

Association with Diabetic Complications

Beyond simply being higher in diabetes, serum endoglin levels have been linked to specific vascular complications. In a study of patients with type 2 diabetes and established coronary artery disease, sEng was independently predictive of major adverse cardiovascular events (MACE) over a 5-year follow-up. Similarly, in diabetic nephropathy, sEng levels increase as kidney function declines, and they are inversely correlated with estimated glomerular filtration rate (eGFR). For diabetic retinopathy, data are more mixed: while some studies report elevated sEng in proliferative retinopathy, others find no difference, possibly because of the dual role of endoglin in retinal angiogenesis. Peripheral arterial disease (PAD) in diabetic patients is also characterized by higher sEng, and it has been suggested that sEng may serve as a surrogate marker for impaired collateral vessel formation.

Endoglin and Endothelial Progenitor Cells

Endoglin is a marker of endothelial progenitor cells (EPCs), which are involved in vascular repair. In diabetes, both the number and function of EPCs are diminished, a phenomenon known as EPC depletion. Serum endoglin may reflect not only the shedding from damaged endothelium but also the reduced capacity for endothelial regeneration. Some researchers propose that measuring sEng alongside circulating CD34+/KDR+ cells provides a more comprehensive picture of vascular health. This dual assessment could improve risk stratification for diabetic patients.

The Role of TGF-β Signaling and Endoglin in Diabetic Endothelial Dysfunction

To understand why serum endoglin levels become elevated in diabetes, it is necessary to examine the TGF-β signaling pathway. In the diabetic milieu, chronic hyperglycemia leads to increased production of TGF-β1 in various tissues, including the vascular endothelium. TGF-β1 is a pleiotropic cytokine that, under normal conditions, helps maintain vascular homeostasis by inhibiting endothelial proliferation and promoting barrier function. However, excessive or sustained TGF-β signaling — particularly through the ALK5-Smad2/3 pathway — can induce endothelial-to-mesenchymal transition (EndMT), promote fibrosis, and impair angiogenesis. Endoglin acts as a buffer: by shifting TGF-β signaling toward the ALK1-Smad1/5 pathway, it counteracts the pro-fibrotic effects of ALK5. In diabetes, the balance is disrupted. Increased MMP-14 activity, induced by inflammatory cytokines such as tumor necrosis factor-α (TNF-α), leads to excessive shedding of endoglin from the cell surface. This reduces the membrane-bound fraction that can co-modulate TGF-β signaling, while simultaneously increasing soluble endoglin that may itself antagonize protective TGF-β signals. The net effect is a shift toward endothelial dysfunction and impaired vascular repair.

Interestingly, a subset of patients with long-standing diabetes without overt complications may have lower serum endoglin levels, possibly due to compensatory downregulation or clearance. This suggests a U-shaped relationship, where both very low and very high sEng levels may be pathological. Longitudinal studies are needed to clarify the trajectory of sEng changes during the progression from prediabetes to complications.

Clinical Utility of Serum Endoglin as a Biomarker

Risk Stratification and Early Detection

One of the most promising applications of serum endoglin measurement is in identifying diabetic patients at high risk for developing vascular complications before clinical signs appear. Since endothelial dysfunction precedes overt organ damage, sEng could serve as an early warning signal. In a prospective study published in Diabetes Care, baseline sEng levels were independently associated with incident nephropathy and cardiovascular events after adjusting for traditional risk factors. Combining sEng with other biomarkers, such as NT-proBNP, hs-CRP, or urinary albumin-to-creatinine ratio, may improve the area under the receiver operating characteristic curve (AUC) for predicting outcomes.

Monitoring Treatment Response

Another area of interest is using changes in serum endoglin to assess the efficacy of interventions. For instance, treatment with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) has been shown to reduce sEng levels in hypertensive diabetic patients, possibly by improving endothelial function. Similarly, statin therapy may lower sEng through anti-inflammatory effects. Metformin, the first-line oral hypoglycemic agent, has been associated with reduced sEng in small studies, but data are inconsistent. The ability to monitor sEng over time could help clinicians tailor therapies and adjust doses in a personalized manner. If a patient's sEng level does not decrease despite intensive risk factor management, that may signal a need for more aggressive or alternative treatments.

Prognosis in Advanced Disease

For patients who already have established vascular complications, serum endoglin may provide prognostic information. In diabetic patients with chronic kidney disease (CKD), sEng levels correlate with the rate of decline in eGFR. Those with sEng levels in the top tertile have a 2.5-fold higher risk of progression to end-stage renal disease. In heart failure with preserved ejection fraction (HFpEF) — a condition increasingly recognized as a diabetic complication — higher sEng is associated with worse symptoms and increased hospitalization rates. Thus, sEng could be integrated into risk scores for multiple diabetes-related outcomes.

Challenges and Limitations in Using Serum Endoglin

Despite the promise, several obstacles must be overcome before serum endoglin can be adopted into routine clinical practice. First, there is no standardized assay for sEng measurement. Different studies use various ELISA kits with different antibodies and calibration, leading to variability in absolute concentrations. A global effort to establish a reference standard and harmonize results is needed. Second, sEng levels can be influenced by factors other than diabetic vascular health. For example, preeclampsia is associated with extremely high sEng, as are some cancers (due to tumor angiogenesis). Hepatic function also affects sEng clearance, as the liver is a primary site of elimination. Therefore, sEng must be interpreted in the context of the patient's overall clinical status. Third, normal reference ranges have not been firmly established across age, sex, and ethnic groups — although some population-based studies suggest median levels around 4–6 ng/mL in healthy adults, these values are only approximations. Finally, longitudinal studies with repeated measurements are scarce; we do not yet know how much sEng fluctuates within an individual over time or what constitutes a clinically meaningful change.

Therapeutic Approaches Targeting Endoglin

The central role of endoglin in TGF-β signaling and angiogenesis makes it an attractive therapeutic target. Several strategies are being explored in preclinical and clinical settings:

  • Inhibition of MMP-14: Since MMP-14 is responsible for shedding endoglin, inhibitors of this protease could reduce sEng levels and preserve membrane-bound endoglin. Small molecules such as TIMP-2 analogs or selective MMP-14 blockers are under development for cancer and could be repurposed for diabetic vascular disease.
  • Modulation of TGF-β signaling: Neutralizing antibodies against TGF-β1 or its receptors (e.g., fresolimumab) have been tested in fibrosis and some vascular diseases. However, systemic blockade of TGF-β carries risks of disrupting immune regulation and wound healing. A more targeted approach might involve enhancing ALK1 signaling downstream of endoglin.
  • Endoglin-trapping agents: Given that soluble endoglin can act as a decoy, developing a drug that binds and neutralizes excess sEng could restore normal TGF-β signaling. This is analogous to the use of VEGF-trap (aflibercept) in ophthalmology.
  • Gene therapy: For individuals with low membrane-bound endoglin (e.g., those with hereditary hemorrhagic telangiectasia, HHT), upregulating endoglin expression may be beneficial. In diabetes, however, the primary problem is excessive shedding, so reducing MMP-14 activity might be more relevant.

Phase II clinical trials using an anti-endoglin monoclonal antibody (TRC105, carotuximab) in cancer patients have shown acceptable safety profiles, although they did not specifically target diabetic complications. These findings support the feasibility of modulating endoglin therapeutically. Future studies should evaluate whether such agents can improve vascular outcomes in diabetic populations, perhaps as an adjunct to standard care.

Future Research Directions

To translate the measurement of serum endoglin from research to clinical practice, several gaps must be addressed. First, large-scale, multi-ethnic prospective cohort studies with standardized assays are needed to define age- and sex-specific reference ranges and to quantify the incremental predictive value of sEng over traditional risk factors. Second, the relationship between sEng and specific diabetic complications should be explored in greater depth using modern imaging techniques (e.g., coronary CT angiography, carotid ultrasound, retinal optical coherence tomography angiography) to correlate sEng with structural vascular changes. Third, the impact of glucose-lowering medications on sEng needs systematic investigation; for instance, SGLT2 inhibitors and GLP-1 receptor agonists have shown remarkable cardiovascular benefits, and it would be informative to know if they modulate sEng levels. Fourth, the possibility of a multi-biomarker panel that includes sEng, homocysteine, ADMA (asymmetric dimethylarginine), and inflammatory markers should be evaluated to improve predictive accuracy. Finally, understanding the biological pathway from hyperglycemia to MMP-14 upregulation and endoglin shedding could uncover new molecular targets for intervention.

Integrating Serum Endoglin into Clinical Practice

Assuming these research questions are answered, the potential implementation of serum endoglin testing could follow a model similar to B-type natriuretic peptide (BNP) for heart failure or high-sensitivity C-reactive protein (hs-CRP) for cardiovascular risk. A simple blood test could be added to annual diabetic assessments for patients without known vascular disease. Those with elevated sEng (e.g., above the 90th percentile for age) would receive intensified risk factor control, more frequent screening for complications (e.g., echocardiogram, ankle-brachial index, retinal exams), and possibly referral to a vascular specialist. For patients with established complications, serial sEng measurements every 6–12 months could track disease progression or response to therapy. The cost of an ELISA-based sEng test is relatively low (comparable to hs-CRP), making it accessible for widespread use. However, until robust evidence of benefit is demonstrated, third-party payers may not reimburse the test. Advocacy by professional societies and inclusion in clinical guidelines will be necessary.

Conclusion

Serum endoglin emerges from a large body of research as a promising biomarker for diabetic vascular dysfunction. Its elevation reflects endothelial stress, dysregulated TGF-β signaling, and ongoing vascular damage. By integrating sEng measurement into the clinical workflow, we may improve early risk stratification, tailor therapeutic strategies, and better monitor disease progression. However, the path from promising biomarker to established clinical tool is long and requires rigorous validation, standardization, and demonstration of clinical utility. Continued investigation into the molecular mechanisms regulating endoglin shedding and the development of targeted therapies may also open new avenues for treating diabetic vascular disease. For now, clinicians should be aware of the mounting evidence and consider serum endoglin as a helpful adjunct in the comprehensive assessment of diabetic patients — particularly those with atypical presentations or unexplained progressive complications.

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