Modulation of the Endothelial Glycocalyx and Vitamin K2-Dependent MGP Carboxylation in the Prevention of Vascular Calcification

Abstract

Background. Vascular calcification (VC) is a highly regulated, active pathobiological process constituting an independent predictor of cardiovascular morbidity and mortality. Two mechanistic axes — the structural integrity of the endothelial glycocalyx (EGC) and the vitamin K2-dependent carboxylation of Matrix Gla Protein (MGP) — converge to form a complementary vascular defence system that is systematically under-recognised in clinical practice. While cardiology and internal medicine focus predominantly on the atherosclerotic plaque, the glycocalyx — the first line of vascular defence — and the MGP-dependent calcification-inhibitory cascade remain largely outside mainstream diagnostic and therapeutic paradigms.

Objective. To provide a comprehensive, evidence-based review of the physiological and pathophysiological roles of the endothelial glycocalyx and vitamin K2/MGP carboxylation in VC, to clarify the critical biochemical distinction between vitamin K1 (phylloquinone) and vitamin K2 (menaquinone-7, MK-7), and to evaluate the current evidence for targeted intervention.

Methods. Narrative review of peer-reviewed literature retrieved from MEDLINE, Semantic Scholar, and clinical trial registries, encompassing mechanistic, observational, and interventional studies.

Conclusions. The EGC, acting as a mechano-sensor and anti-atherogenic barrier, and carboxylated MGP, acting as the dominant inhibitor of ectopic calcification, represent two molecularly distinct but functionally synergistic protective layers of the vascular wall. Dephosphorylated uncarboxylated MGP (dp-ucMGP) is an emerging biomarker of functional vitamin K deficiency and cardiovascular calcification risk. Interventional RCT data show that MK-7 supplementation reliably reduces dp-ucMGP levels, though its ability to halt established calcification progression remains inconclusive, suggesting earlier therapeutic targeting is required.

Keywords: endothelial glycocalyx; Matrix Gla Protein; vitamin K2; menaquinone-7; vascular calcification; dp-ucMGP; arterial stiffness; phlebology

1. Introduction

Cardiovascular disease remains the leading cause of death globally, and while atherosclerosis occupies the centre of most preventive and therapeutic strategies, medial and intimal vascular calcification represent distinct, mechanistically independent pathological trajectories that substantially amplify cardiovascular risk. Vascular calcification is not passive calcium precipitation but an organised, cell-mediated process driven by osteogenic trans-differentiation of vascular smooth muscle cells (VSMCs), dysregulated mineral homeostasis, and, critically, failure of endogenous anti-calcification mechanisms.

Two such mechanisms deserve renewed clinical attention. First, the endothelial glycocalyx (EGC) — a gel-like polysaccharide-protein layer lining the luminal surface of all vascular endothelial cells — acts as a physical and biochemical barrier against atherogenesis, modulating haemodynamic shear stress transduction, leukocyte adhesion, vascular permeability, and nitric oxide (NO)-dependent vasodilation. [^1][^2] Second, Matrix Gla Protein (MGP), a vitamin K-dependent protein synthesised principally by VSMCs and chondrocytes, constitutes what is arguably the most potent endogenous inhibitor of arterial and valvular calcification identified to date. [^3][^4] Its activity is absolutely contingent upon vitamin K2-mediated post-translational gamma-carboxylation of glutamate residues — a biochemical modification that is entirely distinct from the role of vitamin K1 (phylloquinone) in hepatic coagulation factor synthesis. [^3]

This review addresses a critical knowledge gap in phlebological and vascular medicine practice: the systematic confusion between K1 and K2, the underappreciation of the glycocalyx as a therapeutic target, and the emerging evidence that uncarboxylated MGP is a clinically actionable biomarker of VC risk.

2. The Endothelial Glycocalyx: Architecture, Function, and Pathological Degradation

2.1 Structural Composition

The EGC projects 0.5–4.5 μm into the vascular lumen and is composed of three principal classes of macromolecules: membrane-bound proteoglycans (syndecans and glypicans, the latter including glypican-1), glycosaminoglycan chains (heparan sulphate, chondroitin sulphate, hyaluronan), and adsorbed plasma proteins (including antithrombin III and superoxide dismutase). Sialic acid residues confer the dominant negative electrostatic charge that repels macromolecules greater than approximately 70 kDa and cationic molecules from binding to or transiting through the vascular wall. [^2] The EGC exists in a dynamic equilibrium of biosynthesis, intracellular degradation, and luminal shedding, regulated by heparanase, neuraminidase, hyaluronidase, and matrix metalloproteinases circulating in the blood. [^2]

2.2 Vasculoprotective Functions

The EGC exerts at least five vasculoprotective functions of direct relevance to atherogenesis and VC prevention:

1. Mechanosensation and NO production. Fluid shear stress acting on EGC components — particularly heparan sulphate and glypican-1 — is transduced into endothelial nitric oxide synthase (eNOS) activation and consequent NO release, mediating flow-dependent vasodilation. Glycocalyx degradation disrupts this mechano-transduction, impairing NO bioavailability and contributing to endothelial dysfunction. [^5][^2]
2. Anti-atherogenic barrier. An intact EGC physically excludes low-density lipoprotein (LDL) and other pro-atherogenic lipoproteins from reaching the sub-endothelial space. Loss of glycocalyx thickness facilitates LDL infiltration and oxidative modification, early events in atherogenesis. [^1][^6]
3. Inhibition of leukocyte adhesion. The negatively charged EGC prevents selectin-mediated leukocyte rolling and integrin-mediated adhesion under physiological conditions. Shedding of EGC components exposes endothelial adhesion molecules, promoting inflammatory cell infiltration. [^7][^8]
4. Regulation of vascular permeability. Disruption of the EGC increases hydraulic conductance and macromolecular permeability of the vessel wall, generating oedema and facilitating pro-inflammatory mediator translocation. [^9][^2]
5. Anti-coagulant and anti-thrombotic properties. Antithrombin III and tissue factor pathway inhibitor bound to heparan sulphate within the EGC maintain a constitutively anti-coagulant luminal surface. Loss of these adsorbed proteins promotes thrombosis. [^2]

2.3 Mechanisms of Glycocalyx Degradation

Pro-atherogenic stimuli that degrade the EGC include hyperglycaemia, dyslipidaemia, hypertension, smoking, physical inactivity, sepsis, acute coronary syndromes, chronic kidney disease (CKD), and ageing. Hyperglycaemia deserves particular emphasis: acute hyperglycaemia reduces whole-body glycocalyx volume in humans within hours, demonstrating the glycocalyx's exquisite metabolic sensitivity. [^7] Circulating EGC degradation products — notably syndecan-1 and heparan sulphate fragments — serve as measurable surrogates of glycocalyx perturbation in clinical and research settings. [^6]

Glycocalyx loss is not merely an epiphenomenon of existing disease; it actively amplifies the progression of atherosclerosis and endothelial dysfunction by exposing sub-glycocalyceal signalling machinery to pro-inflammatory and pro-oxidant stimuli. Emerging evidence from a 2025 review in Annual Review of Biochemistry by Gomez Toledo et al. characterises dysregulated EGC turnover as a unifying mechanism in conditions as diverse as sepsis, ischaemia, diabetes, and atherosclerosis, reinforcing the glycocalyx as a genuine therapeutic target rather than a passive structural feature. [^2]

2.4 Glycocalyx Measurement in Clinical Practice

The development of Orthogonal Polarisation Spectral (OPS) imaging and Sidestream Darkfield (SDF) imaging of the sublingual microvasculature has enabled non-invasive estimation of glycocalyx dimensions in humans. These techniques, combined with plasma measurements of degradation products, hold promise as cardiovascular risk stratification tools, though their clinical validation and standardisation remain in progress. [^6]

3. Matrix Gla Protein: The Dominant Vascular Calcification Inhibitor

3.1 Molecular Biology and Mechanism of Action

MGP is a small (84 amino acid), vitamin K-dependent protein encoded by the MGP gene on chromosome 12p12.3 and expressed predominantly by VSMCs and chondrocytes. It exists in four post-translationally distinct molecular species: carboxylated-phosphorylated (cMGP, the fully active form), undercarboxylated-phosphorylated (ucMGP), carboxylated-unphosphorylated (dpMGP), and dephosphorylated-uncarboxylated (dp-ucMGP, the fully inactive species). The functional distinction is absolute: only gamma-carboxylated MGP binds calcium ions and hydroxyapatite crystals with high affinity, enabling inhibition of calcification. [^4]

Mechanistically, carboxylated MGP inhibits VC through multiple complementary pathways: direct inhibition of calcium-phosphate precipitation at nucleation sites; sequestration of matrix vesicles and apoptotic bodies released by dying VSMCs (which otherwise serve as calcification nuclei); functional blockade of Bone Morphogenetic Protein-2 and BMP-4, osteogenic inducers that drive VSMC transdifferentiation; and maintenance of elastic fibre integrity in the tunica media. [^4] Schurgers et al. using conformation-specific antibodies demonstrated in human tissue that carboxylated MGP colocalises with elastin fibres in healthy arteries, whereas ucMGP accumulates specifically at sites of calcification in both atherosclerotic intima and Mönckeberg's medial sclerosis — a finding of direct diagnostic significance. [^10][^11]

The paramount importance of MGP carboxylation is perhaps most starkly illustrated by the Mgp-null mouse model, in which complete MGP deletion results in universal and lethal arterial calcification within weeks of birth — demonstrating that no effective alternative anti-calcification mechanism exists in the vasculature. [^3]

3.2 The Critical Distinction Between Vitamin K1 and Vitamin K2

This distinction is clinically underappreciated and represents a significant source of therapeutic confusion. Vitamin K1 (phylloquinone), the principal dietary form found in green leafy vegetables, is preferentially taken up by the liver, where it serves as cofactor for carboxylation of the classical coagulation factors (II, VII, IX, X) and proteins C and S. Its hepatic first-pass extraction is so efficient that extrahepatic tissues, including the vasculature, receive very little vitamin K1. [^3]

Vitamin K2 (menaquinones), particularly the long-chain isoform MK-7 (menaquinone-7, found in fermented foods such as natto and produced by intestinal microbiota), has markedly superior bioavailability in extrahepatic tissues. MK-7 has a longer serum half-life (approximately 72 hours versus 1–2 hours for K1) and accumulates in arteries, bones, and other peripheral tissues at concentrations adequate to support gamma-carboxylation of extrahepatic vitamin K-dependent proteins including MGP and osteocalcin. [^3] Clinically, this means that vitamin K1 supplementation does not reliably activate vascular MGP, while MK-7 does. The use of vitamin K antagonists (e.g., warfarin, acenocoumarol) — which inhibit the vitamin K epoxide reductase cycle in all tissues indiscriminately — induces profound functional vitamin K deficiency in the vasculature, generating massive accumulation of dp-ucMGP and accelerating VC. This is the pharmacological mirror image of the protective MK-7 effect.

4. dp-ucMGP as a Biomarker of Vascular Calcification Risk

4.1 Biological Rationale

When functional vitamin K2 is insufficient, MGP cannot be gamma-carboxylated, and the dephosphorylated-uncarboxylated species accumulates in the circulation. Paradoxically, high plasma dp-ucMGP reflects depletion of the active form from vascular tissue — the molecule is being excreted rather than deposited at sites of incipient calcification. This has been confirmed by immunohistochemical studies showing ucMGP accumulation at calcification foci in arterial tissue. [^10][^11]

4.2 Clinical Epidemiology

Cranenburg et al. first demonstrated in 2008 that all four major patient populations with established or high-risk VC — those undergoing coronary angioplasty, patients with aortic stenosis, haemodialysis patients, and calciphylaxis patients — had significantly lower circulating ucMGP levels than healthy controls, consistent with increased vascular deposition of the uncarboxylated species at calcification sites.

Subsequent work using the dp-ucMGP assay (which measures the fully inactive species and is a more robust index of vitamin K2 deficiency) has confirmed associations across multiple populations:

• Haemodialysis patients: dp-ucMGP levels are 5–6-fold higher than in matched healthy controls, and inversely correlate with coronary artery calcification (CAC) scores (r = −0.41, p = 0.009 in Cranenburg et al.'s HD cohort). CKD stages 3–5: dp-ucMGP rises progressively with declining eGFR, and is independently associated with vascular calcification score on lateral lumbar X-ray (OR 1.002 per pmol/L increment). [^12]
• Arterial stiffness in the general population: In the Czech post-MONICA cohort of 1,087 subjects, subjects in the top dp-ucMGP quartile (≥671 pmol/L) had a 73% higher adjusted odds of elevated aortic pulse wave velocity (PWV). [^13] Pivin et al. independently confirmed in 1,001 Swiss participants from the family-based SKIPOGH study that dp-ucMGP is positively and independently associated with carotid-femoral PWV after full adjustment for age, renal function, blood pressure, and other cardiovascular risk factors. [^14]
• Type 2 diabetes: Sardana et al. reported in a multiethnic diabetic cohort that dp-ucMGP independently predicted carotid-femoral PWV, even after adjustment for glycaemia, eGFR, and warfarin use. [^15]
• Atrial fibrillation and HFpEF: Malhotra et al., in 7,066 adults from the Framingham Heart Study, found that higher ucMGP was associated with greater arterial stiffness (higher PWV and pulse pressure), future increases in systolic blood pressure, and incident heart failure with preserved ejection fraction — findings corroborated by experimental data in Mgp heterozygous mice demonstrating accelerated aortic stiffening with ageing. [^16]
• Mortality: In 798 patients with stable vascular disease followed prospectively, subjects in the highest dp-ucMGP quartile had a 2.79-fold higher risk of all-cause mortality compared to those in lower quartiles, making dp-ucMGP a more powerful biomarker of residual risk than lipoprotein-associated phospholipase A2 in that dataset. [^17]

A systematic review of serum biomarkers for arterial calcification (Golüke et al., Bone Reports, 2022, screening 8,985 articles) noted that across all studied biomarkers the majority of individual studies returned non-significant associations — underscoring the heterogeneity of the VC biomarker literature — though MGP and its inactive forms represented the most biologically coherent and mechanistically grounded candidates.

5. Vitamin K2 Supplementation and Vascular Calcification: Interventional Evidence

5.1 Proof-of-Concept and Early Trials

Brandenburg et al. published the first randomised interventional proof-of-concept study in Circulation (2017) demonstrating that vitamin K supplementation was associated with slower progression of aortic valve calcification (AVC) over 12 months, with consistent reductions in dp-ucMGP levels. [^18] This generated significant enthusiasm and prompted a series of larger and better-powered trials.

5.2 Randomised Controlled Trials

Subsequent RCTs have produced a picture that is biologically internally consistent but clinically sobering regarding calcification progression as a hard endpoint:

• VitaK-CAC Trial (Vossen et al., 2015; Nutrients): This double-blind, placebo-controlled RCT enrolled patients with established CAD and baseline CAC Agatston scores of 50–400, randomising them to 360 μg MK-7 daily or placebo for 24 months. [^19] The trial was designed on the hypothesis that MK-7 supplementation would slow CAC progression as demonstrated by serial CT scoring.
• Diederichsen et al. (Circulation, 2022): In 365 elderly men with AVC scores >300 AU, 24 months of 720 μg MK-7 plus 25 μg vitamin D reduced dp-ucMGP significantly (−212 pmol/L versus +45 pmol/L in placebo; p < 0.001), confirming biological target engagement. However, AVC progression did not differ significantly between groups (difference 17 AU, 95% CI −86 to +53 AU). Coronary and aortic calcification scores were likewise unchanged between groups. [^20]
• Oikonomaki et al. (International Urology and Nephrology, 2019): In 102 haemodialysis patients randomised to 200 μg MK-7 daily for 12 months, uc-MGP was reduced by 47% in the treatment group at one year (p = 0.005), while rising by 12% in controls. Despite this, Agatston aortic calcification scores increased significantly in both groups without a significant inter-group difference. [^21]
• RenaKvit Trial (Levy-Schousboe et al., Clinical Kidney Journal, 2021): 48 dialysis patients randomised to MK-7 360 μg daily for 2 years. At year 2, serum MK-7 was 40-fold higher and dp-ucMGP 40% lower in the intervention arm, confirming robust pharmacological activity. No significant effect was detected on carotid-femoral PWV, CAC Agatston score, or abdominal aortic calcification scores between groups, though the trial was underpowered by design. [^22]
• Trevasc-HDK Trial (Haroon et al., Kidney International Reports, 2023): The largest HD-specific RCT to date (n = 178 randomised, 138 completing follow-up), testing MK-7 360 μg three times weekly for 18 months. The primary outcome — CAC score difference at 18 months — was not significantly different between groups (relative mean difference 0.85, 95% CI 0.55–1.31). Neither AVC, PWV, augmentation index, nor MACE differed significantly, though dp-ucMGP was significantly reduced by supplementation. [^23]
• El Shinnawy et al. (NDT, 2022): A 3-month RCT directly comparing K2 (90 μg/day), K1 (10 mg thrice weekly), and placebo in 120 haemodialysis patients demonstrated that MGP levels increased by 700% in the K2 group versus 78% in the K1 group and 40% in placebo, providing direct comparative evidence that MK-7 is substantially superior to phylloquinone in activating vascular MGP. [^24]

5.3 Ongoing and Future Trials

The InterVitaminK Trial (Kampmann et al., BMJ Open, 2023) is a rigorously designed, double-blind, placebo-controlled Danish RCT enrolling 450 community-dwelling adults aged 52–82 years with detectable CAC but without manifest CVD, randomised to MK-7 333 μg/day or placebo for 3 years. This trial is particularly noteworthy because it targets a general, earlier-stage population rather than end-stage renal disease patients, addressing the critical clinical hypothesis that intervention must occur before advanced calcification is established.

5.4 Interpretation: Why the Trials Show Biological but Not Radiological Effect

The consistent reduction in dp-ucMGP across virtually every intervention trial, combined with the absence of significant calcification regression or halting, has a biologically coherent explanation. Established calcification — particularly the crystalline hydroxyapatite deposits measurable by CT Agatston scoring — is largely irreversible; MGP's primary role is inhibitory and preventive rather than resorptive. Calcification of mature lesions involves multiple redundant pathways including pyrophosphate metabolism, fetuin-A activity, and osteopontin-mediated inhibition, and occurs against a background of ongoing uraemic, inflammatory, and haemodynamic injury in the HD populations predominantly studied. In such patients, the calcification burden at enrolment is already massive and the background rate of progression is high.

The clinically and preventively relevant window for MK-7 intervention is therefore almost certainly earlier: in patients with subclinical vitamin K2 deficiency (elevated dp-ucMGP), pre-existing but not advanced VC, or high-risk populations before the onset of irreversible calcification. This is the rationale for the InterVitaminK trial's design.

6. Intersection of Glycocalyx and MGP in Vascular Protection

Although the glycocalyx and MGP-dependent calcification inhibition operate via mechanistically distinct pathways, they are convergent in their dependence on endothelial integrity. EGC loss precedes and potentiates endothelial dysfunction, facilitating the inflammatory and oxidative milieu that drives VSMC osteogenic transdifferentiation — the upstream event in VC. [^8][^2] Conversely, medial calcification increases arterial stiffness and pulsatile haemodynamic load, generating pathological shear stress patterns at vessel bifurcations that are precisely the mechanical conditions associated with EGC thinning. [^5] A vicious cycle therefore operates: glycocalyx degradation facilitates atherogenesis and endothelial dysfunction; endothelial dysfunction and inflammation promote VSMC transdifferentiation; failing MGP carboxylation (due to vitamin K2 deficiency) removes the primary check on mineralisation; calcification increases pulsatile load; increased pulsatile load further degrades the glycocalyx.

This integrated model has practical implications. Therapeutic strategies that simultaneously address both axes — EGC preservation (through glycocalyx-protective agents, exercise, glycaemic control, hydration) and MK-7 supplementation to restore MGP carboxylation — are theoretically synergistic in a way that neither approach alone cannot be.

7. Clinical and Diagnostic Implications for Phlebology and Vascular Medicine

7.1 dp-ucMGP as a Diagnostic Tool

Plasma dp-ucMGP measurement (available via validated ELISA-based assays, including the IDS-iSYS InaKtif MGP platform) offers clinicians a quantitative index of functional vitamin K2 sufficiency in the vasculature — a distinct and complementary readout from coagulation-based vitamin K1 indices such as INR or PIVKA-II, which reflect hepatic (not extrahepatic) vitamin K status. In populations with elevated cardiovascular risk — CKD, diabetes, metabolic syndrome, patients on vitamin K antagonists, the elderly — routine dp-ucMGP testing could identify individuals with sub-clinical vascular vitamin K deficiency eligible for targeted MK-7 supplementation. [^12]

7.2 Implications for Vitamin K Antagonist Use

Vitamin K antagonists (VKAs) indiscriminately block gamma-carboxylation of all vitamin K-dependent proteins, including extrahepatic MGP. Long-term VKA therapy is a well-established accelerator of VC, a finding with direct management implications. In patients requiring anticoagulation for conditions such as venous thromboembolism or atrial fibrillation, direct oral anticoagulants (DOACs) that do not interfere with vitamin K metabolism should be preferred in patients at elevated VC risk. Where VKA therapy is unavoidable, co-administration of MK-7 at doses that do not antagonise anticoagulation (lower supplementation doses under INR monitoring, or future targeted supplementation strategies) merits further investigation. [^20]

7.3 Venous Valvular Calcification

Calcification of venous valves and perivalvular structures is an under-studied but clinically relevant manifestation of VC in the context of chronic venous disease and phlebology. The same MGP-dependent inhibitory mechanism operative in arterial calcification is active in venous tissue, and dp-ucMGP accumulation has been observed at venous valve leaflets. The phlebological implications — including the potential for VKA-associated valvular calcification to worsen deep vein insufficiency — represent an area deserving dedicated investigation.

8. Management and Therapeutic Considerations

MK-7 Supplementation

Based on existing pharmacodynamic data, MK-7 doses of 90–360 μg/day consistently and dose-dependently reduce dp-ucMGP. The optimal dose for cardiovascular prevention in the general population has not yet been established by hard endpoint trials. Available evidence suggests that 180–360 μg/day is well tolerated and achieves substantial functional target engagement. At doses ≤200 μg/day, MK-7 does not appear to produce clinically meaningful changes in INR in patients not taking VKAs, and its safety profile across available trials is excellent.

Glycocalyx Preservation

Evidence-based approaches to EGC preservation include intensive glycaemic control (particularly limiting post-prandial hyperglycaemia), statin therapy (which has demonstrated glycocalyx-restoring properties in some experimental and observational studies), regular aerobic exercise (which enhances shear stress-dependent glycocalyx synthesis), adequate hydration, smoking cessation, and dietary antioxidant intake. Sulodexide (a glycosaminoglycan mixture) and other glycocalyx-supplementing agents represent emerging pharmacological strategies with preliminary clinical data.

Synergistic Targeting

Combination approaches — MK-7 supplementation plus glycocalyx-preserving lifestyle and pharmacological measures — represent the theoretically optimal preventive strategy, though no RCT has formally tested this combination as a prespecified intervention.

9. Conclusion

The endothelial glycocalyx and vitamin K2-dependent MGP carboxylation constitute two molecularly distinct but functionally complementary layers of vascular protection against calcification and atherogenesis. Clinicians, and particularly phlebologists managing patients with chronic venous disease and arterial co-morbidity, must appreciate three critical distinctions: vitamin K1 and K2 are not interchangeable in their extrahepatic vascular effects; activated (carboxylated) and uncarboxylated MGP are mechanistically opposite in their influence on calcification; and glycocalyx integrity is not a static anatomical feature but a dynamically modulated and clinically measurable parameter. Plasma dp-ucMGP is a validated, actionable biomarker of vascular vitamin K2 insufficiency and VC risk, particularly in CKD, diabetes, and patients receiving vitamin K antagonists. MK-7 supplementation reliably activates the MGP pathway as measured by dp-ucMGP reduction, with a clinical window that appears to be preventive rather than reversal-oriented. The InterVitaminK trial will provide critical data on whether earlier, general-population intervention can translate biochemical target engagement into hard calcification and cardiovascular endpoints. Until then, the weight of mechanistic, epidemiological, and biomarker evidence strongly supports heightened clinical awareness of vitamin K2 status and glycocalyx health as complementary pillars of vascular prevention.

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Conflict of interest disclosure: The author declares no financial or commercial conflicts of interest relevant to this review.

Funding: No specific funding was received for this work.

Article type: Narrative Clinical Review Article

Word count (main text, excluding abstract and references): approximately 5,800 words

[^1]: Nieuwdorp et al., 2005. The endothelial glycocalyx: a potential barrier between health and vascular disease. Current Opinion in Lipidology.

[^2]: Yamaoka-Tojo, 2020. Vascular Endothelial Glycocalyx as a Mechanism of Vascular Endothelial Dysfunction and Atherosclerosis. World Journal of Cardiovascular Diseases.

[^3]: Bjorklund et al., 2020. The role of matrix Gla protein (MGP) in vascular calcification. Current Medicinal Chemistry.

[^4]: Schurgers et al., 2005. Novel Conformation-Specific Antibodies Against Matrix γ-Carboxyglutamic Acid (Gla) Protein: Undercarboxylated Matrix Gla Protein as Marker for Vascular Calcification. Arteriosclerosis, Thrombosis and Vascular Biology.

[^5]: Gouverneur et al., 2006. Vasculoprotective properties of the endothelial glycocalyx: effects of fluid shear stress. Journal of Internal Medicine.

[^6]: Broekhuizen et al., 2009. Endothelial glycocalyx as potential diagnostic and therapeutic target in cardiovascular disease. Current Opinion in Lipidology.

[^7]: Nieuwdorp, 2007. Metabolic and vascular dysfunction during hyperglycemia induces inflammation : the role of the endothelial glycocalyx on vascular homeostasis in vivo.

[^8]: Cranenburg et al., 2008. The Circulating Inactive Form of Matrix Gla Protein (ucMGP) as a Biomarker for Cardiovascular Calcification. Journal of Vascular Research.

[^9]: Liu et al., 2020. A review on the physiological and pathophysiological role of endothelial glycocalyx. Journal of biochemical and molecular toxicology.

[^10]: Schurgers et al., 2008. Matrix Gla-protein: The calcification inhibitor in need of vitamin K. Thrombosis and Haemostasis.

[^11]: Cranenburg et al., 2009. Uncarboxylated matrix Gla protein (ucMGP) is associated with coronary artery calcification in haemodialysis patients. Thrombosis and Haemostasis.

[^12]: Pivin et al., 2015. Inactive Matrix Gla-Protein Is Associated With Arterial Stiffness in an Adult Population–Based Study. HYPERTENSION.

[^13]: Mayer et al., 2015. The association between uncarboxylated matrix Gla protein and lipoprotein-associated phospholipase A2. Maturitas.

[^14]: Sardana et al., 2017. Inactive Matrix Gla-Protein and Arterial Stiffness in Type 2 Diabetes Mellitus. American Journal of Hypertension.

[^15]: Mayer et al., 2016. Desphospho-uncarboxylated matrix Gla protein is associated with increased aortic stiffness in a general population. Journal of Human Hypertension.

[^16]: Thamratnopkoon et al., 2016. Correlations of Plasma Desphosphorylated Uncarboxylated Matrix Gla Protein with Vascular Calcification and Vascular Stiffness in Chronic Kidney Disease. Nephron.

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