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Cees Vermeer - One of the best experts on this subject based on the ideXlab platform.
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Inactive Matrix Gla Protein, Arterial Stiffness, and Endothelial Function in African American Hemodialysis Patients
2019Co-Authors: Mary Ellen Fain, Cees Vermeer, Gaston Kapuku, William Paulson, Celestine Williams, Anas Raed, Yanbin Dong, Marjo Knapen, Norman K. PollockAbstract:AbstractBACKGROUND: Matrix Gla Protein (MGP) is a vascular calcification inhibitor dependent upon vitamin K for activation. Evidence suggests that elevated plasma inactive MGP levels (desphospho-uncarboxylated MGP, dp-ucMGP; indicating poorer vascular vitamin K status) are associated with greater cardiovascular disease (CVD) risk. Despite African Americans experiencing highest rates of kidney failure and CVD events, relationships between dp-ucMGP and CVD risk markers have not been examined in this population. We investigated vascular vitamin K status (via plasma dp-ucMGP) between African American hemodialysis (HD) patients and healthy controls, and the associations of dp-ucMGP with arterial stiffness and endothelial function in HD patients only.METHODS: In 37 African American HD patients and 37 age- and race-matched controls, plasma dp-ucMGP was measured by enzyme immunoassay as a marker of vascular vitamin K status. Carotid-femoral pulse wave velocity (PWV; arterial stiffness measurement) and brachial artery flow-mediated dilation (FMD; endothelial function measurement) were assessed by applanation tonometry and ultrasound, respectively, in HD patients only.RESULTS: Mean dp-ucMGP levels were 5.6 times higher in HD patients vs. controls (2,139 ± 1,102 vs. 382 ± 181 pmol/l, P < 0.01). Multiple linear regression, adjusting for age, sex, dialysis vintage, diabetes mellitus, CVD history, body mass index, and blood pressure, revealed that dp-ucMGP was independently related to PWV (standardized β = 0.49) and FMD (standardized β = -0.53) (both P < 0.01).CONCLUSIONS: Our data suggest that the higher plasma dp-ucMGP concentrations found in African American HD patients may be associated with greater arterial stiffness and endothelial dysfunction.
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Aldosterone, inactive matrix Gla-Protein, and large artery stiffness in hypertension.
2018Co-Authors: Julio A. Chirinos, Mayank Sardana, Amer Ahmed Syed, Maheshwara Reddy Koppula, Swapna Varakantam, Izzah Vasim, Harold G. Oldland, Timothy S. Phan, Nadja E.a. Drummen, Cees VermeerAbstract:Abstract Vascular calcification leads to increased large artery stiffness. Matrix Gla-Protein (MGP) is a vitamin K–dependent Protein that inhibits arterial calcification. Aldosterone promotes vascular calcification and stiffness, but the relationships between aldosterone, MGP, and arterial stiffness are unknown. We studied 199 adults (predominantly older men) with hypertension. We assessed the relationship between levels of dephospho-uncarboxylated MGP (dp-ucMGP), aldosterone, and carotid-femoral pulse wave velocity (CF-PWV) using standard regression and mediation analyses. Plasma aldosterone was measured in a subgroup of subjects (n = 106). Aldosterone was strongly associated with dp-ucMGP (standardized β = 0.50, P
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matrix Gla Protein plaque stability and cardiovascular events in patients with severe atherosclerotic disease
2018Co-Authors: Sabine R Zwakenberg, Cees Vermeer, Joline W J Beulens, Yvonne T Van Der Schouw, Gerard Pasterkamp, Hester Den M RuijterAbstract:Objective This study aims to investigate whether plasma matrix Gla Protein (MGP) species, desphospho-uncarboxylated (dp-uc) MGP, and total uncarboxylated (t-uc) MGP are associated with plaque levels of uncarboxylated (uc) MGP, markers of plaque stability, and cardiovascular disease (CVD) risk. Methods From the Athero-Express biobank, we selected carotid plaque samples of 100 patients who underwent carotid endarterectomy. The level of agreement between plasma MGP species and plaque ucMGP levels was assessed using weighted kappa (κ). We analyzed histological characteristics of plaque composition (plaque hemorrhage, lipid and calcification content). Logistic regression analyses were used to assess the association between plasma MGP and plaque characteristics. Furthermore, CVD endpoints (n = 20) were collected over a mean follow-up of 2.6 years. Results Weighted κ statistics of plasma dp-ucMGP and t-ucMGP and plaque ucMGP were 0.10 (95% CI -0.31 to 0.52) and 0.14 (95% CI -0.20 to 0.48). Higher dp-ucMGP levels tended to be associated with less plaque hemorrhage (ORper 500 nM 0.96; 95% CI 0.92-1.00). No association was found for lipid and calcification content. Cox proportional hazards models showed no association between dp-ucMGP (HRper 200 pM 0.92; 95% CI 0.75-1.11) and an inverse association between t-ucMGP (HRper 500 nM 0.79; 95% CI 0.62-0.99) and cardiovascular events. Conclusions Plasma dp-ucMGP and t-ucMGP concentrations do not reflect plaque ucMGP levels. Elevated dp-ucMGP levels may be associated with less plaque hemorrhage, suggestive of more stable plaques. T-ucMGP was not related with markers of plaque stability; however, elevated plasma t-ucMGP levels were associated with a reduced CVD risk.
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vitamin k dependent carboxylation of matrix Gla Protein influences the risk of calciphylaxis
2017Co-Authors: Sagar U Nigwekar, Cees Vermeer, Sarah L. Booth, D Bloch, Rosalynn M Nazarian, Dihua Xu, Ravi Thadhani, Rajeev MalhotraAbstract:Matrix Gla Protein (MGP) is a potent inhibitor of vascular calcification. The ability of MGP to inhibit calcification requires the activity of a vitamin K–dependent enzyme, which mediates MGP carboxylation. We investigated how MGP carboxylation influences the risk of calciphylaxis in adult patients receiving dialysis and examined the effects of vitamin K deficiency on MGP carboxylation. Our study included 20 patients receiving hemodialysis with calciphylaxis (cases) and 20 patients receiving hemodialysis without calciphylaxis (controls) matched for age, sex, race, and warfarin use. Cases had higher plasma levels of uncarboxylated MGP (ucMGP) and carboxylated MGP (cMGP) than controls. However, the fraction of total MGP that was carboxylated (relative cMGP concentration = cMGP/[cMGP + uncarboxylated MGP]) was lower in cases than in controls (0.58±0.02 versus 0.69±0.03, respectively; P =0.003). In patients not taking warfarin, cases had a similarly lower relative cMGP concentration. Each 0.1 unit reduction in relative cMGP concentration associated with a more than two-fold increase in calciphylaxis risk. Vitamin K deficiency associated with lower relative cMGP concentration in multivariable adjusted analyses ( β =−8.99; P =0.04). In conclusion, vitamin K deficiency–mediated reduction in relative cMGP concentration may have a role in the pathogenesis of calciphylaxis. Whether vitamin K supplementation can prevent and/or treat calciphylaxis requires further study.
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inactive matrix Gla Protein and arterial stiffness in type 2 diabetes mellitus
2017Co-Authors: Mayank Sardana, Amer Ahmed Syed, Maheshwara Reddy Koppula, Swapna Varakantam, Izzah Vasim, Nadja E.a. Drummen, Uzma Kewan, Ali Tariq, Melissa Beraun, Cees VermeerAbstract:BACKGROUND Large artery stiffness is increased in diabetes mellitus and causes an excessive pulsatile load to the heart and to the microvasculature. The identification of pathways related to arterial stiffness may provide novel therapeutic targets to ameliorate arterial stiffness in diabetes. Matrix Gla-Protein (MGP) is an inhibitor of vascular calcification. Activation of MGP is vitamin K dependent. We hypothesized that levels of inactive MGP (dephospho-uncarboxylated MGP; dp-ucMGP) are related to arterial stiffness in type 2 diabetes. METHODS We enrolled a multiethnic cohort of 66 participants with type 2 diabetes. Carotid-femoral pulse wave velocity (CF-PWV) was measured with high-fidelity arterial tonometry (Sphygmocor Device). Dp-ucMGP was measured with ELISA (VitaK; The Netherlands). RESULTS The majority of the participants were middle-aged (62 ± 12 years), male (91%), and had a history of hypertension (82%). Average hemoglobin A1C was 7.2% (55 mmol/mol). Mean dp-ucMGP was 624 ± 638 pmol/l and mean CF-PWV was 11 ± 4 m/sec. In multivariable analyses, dp-ucMGP was independently related to African American ethnicity (β = -0.24, P = 0.005), warfarin use (β = 0.56, P < 0.001), and estimated glomerular filtration rate (eGFR, β = -0.32, P < 0.001). Dp-ucMGP predicted CF-PWV (β = 0.40, P = 0.011), even after adjustment for age, gender, ethnicity, mean arterial pressure, eGFR, and warfarin use. CONCLUSIONS In our cross-sectional analysis, circulating dp-ucMGP was independently associated with CF-PWV in type 2 diabetes. This suggests that deficient vitamin K-dependent activation of MGP may lead to large artery stiffening and could be targeted with vitamin K supplementation in the patients with diabetes.
Kristina I. Boström - One of the best experts on this subject based on the ideXlab platform.
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Matrix Gla Protein regulates differentiation of endothelial cells derived from mouse embryonic stem cells.
2015Co-Authors: Jiayi Yao, Kristina I. Boström, Pierre J. Guihard, Ana M. Blazquez-medela, Yina Guo, Ting Liu, Yucheng YaoAbstract:Matrix Gla Protein (MGP) is an antagonist of bone morphogenetic Proteins and expressed in vascular endothelial cells. Lack of MGP causes vascular abnormalities in multiple organs in mice. The objective of this study is to define the role of MGP in early endothelial differentiation. We find that expression of endothelial markers is highly induced in Mgp null organs, which, in wild type, contain high MGP expression. Furthermore, Mgp null embryonic stem cells express higher levels of endothelial markers than wild-type controls and an abnormal temporal pattern of expression. We also find that the Mgp-deficient endothelial cells adopt characteristics of mesenchymal stem cells. We conclude that loss of MGP causes dysregulation of early endothelial differentiation.
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reducing jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla Protein deficiency
2013Co-Authors: Yucheng Yao, Medet Jumabay, Jiayi Yao, Pierre J. Guihard, Melina Radparvar, Ana M Blazquezmedela, Kristina I. BoströmAbstract:Cerebral arteriovenous malformations (AVMs) are common vascular malformations, which may result in hemorrhagic strokes and neurological deficits. Bone morphogenetic Protein (BMP) and Notch signaling are both involved in the development of cerebral AVMs, but the cross-talk between the two signaling pathways is poorly understood. Here, we show that deficiency of matrix Gla Protein (MGP), a BMP inhibitor, causes induction of Notch ligands, dysregulation of endothelial differentiation, and the development of cerebral AVMs in MGP null (Mgp−/−) mice. Increased BMP activity due to the lack of MGP induces expression of the activin receptor-like kinase 1, a BMP type I receptor, in cerebrovascular endothelium. Subsequent activation of activin receptor-like kinase 1 enhances expression of Notch ligands Jagged 1 and 2, which increases Notch activity and alters the expression of Ephrin B2 and Ephrin receptor B4, arterial and venous endothelial markers, respectively. Reducing the expression of Jagged 1 and 2 in the Mgp−/− mice by crossing them with Jagged 1 or 2 deficient mice reduces Notch activity, normalizes endothelial differentiation, and prevents cerebral AVMs, but not pulmonary or renal AVMs. Our results suggest that Notch signaling mediates and can modulate changes in BMP signaling that lead to cerebral AVMs.
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Matrix Gla Protein deficiency causes arteriovenous malformations in mice
2011Co-Authors: Yucheng Yao, Medet Jumabay, Anthony Wang, Kristina I. BoströmAbstract:Arteriovenous malformations (AVMs) in organs, such as the lungs, intestine, and brain, are characteristic of hereditary hemorrhagic telangiectasia (HHT), a disease caused by mutations in activin-like kinase receptor 1 (ALK1), which is an essential receptor in angiogenesis, or endoglin. Matrix Gla Protein (MGP) is an antagonist of BMPs that is highly expressed in lungs and kidneys and is regulated by ALK1. The objective of this study was to determine the role of MGP in the vasculature of the lungs and kidneys. We found that Mgp gene deletion in mice caused striking AVMs in lungs and kidneys, where overall small organ size contrasted with greatly increased vascularization. Mechanistically, MGP deficiency increased BMP activity in lungs. In cultured lung epithelial cells, BMP-4 induced VEGF expression through induction of ALK1, ALK2, and ALK5. The VEGF secretion induced by BMP-4 in Mgp-/- epithelial cells stimulated proliferation of ECs. However, BMP-4 inhibited proliferation of lung epithelial cells, consistent with the increase in pulmonary vasculature at the expense of lung tissue in the Mgp-null mice. Similarly, BMP signaling and VEGF expression were increased in Mgp-/- mouse kidneys. We therefore conclude that Mgp gene deletion is what we believe to be a previously unidentified cause of AVMs. Because lack of MGP also causes arterial calcification, our findings demonstrate that the same gene defect has drastically different effects on distinct vascular beds.
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heat shock Protein 70 enhances vascular bone morphogenetic Protein 4 signaling by binding matrix Gla Protein
2009Co-Authors: Yucheng Yao, Andrew D Watson, Kristina I. BoströmAbstract:Rationale: Matrix Gla Protein (MGP) is a calcification inhibitor, which binds and inhibits bone morphogenetic Protein (BMP)-2 and -4. Objective: The objective was to determine whether MGP also binds other Proteins, which could interfere with its function. Methods and Results: We transfected bovine aortic endothelial cells with N-terminally FLAG-tagged MGP and used immunoprecipitation and liquid chromatographic–tandem mass spectrometric analysis to identify MGP-binding Proteins. Heat shock Protein (HSP)70, a stress-induced Protein expressed in atherosclerotic lesions and soluble in serum, was identified as a novel MGP-binding Protein. The interaction between MGP and HSP70 was confirmed by coimmunoprecipitation and chemical crosslinking, and blocked the interaction between MGP and BMP-4. In endothelial cells, HSP70 enhanced BMP-4–induced proliferation and tube formation, and in calcifying vascular cells, HSP70 enhanced BMP-induced calcium deposition. In addition, HSP70 mediated the procalcific effect of interleukin-6 on calcifying vascular cells. In apolipoProtein E–null mice, a model for atherosclerosis, levels of BMP-4, HSP70, MGP, and interleukin-6 were elevated in the aortic wall. Levels of BMP-4, HSP70, and interleukin-6 were also elevated in serum, and anti-HSP70 antibodies diminished its procalcific effect on calcifying vascular cells. Conclusion: HSP70 binds MGP and enhances BMP activity, thereby functioning as a potential link between cellular stress, inflammation, and BMP signaling.
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Proline and γ-Carboxylated Glutamate Residues in Matrix Gla Protein Are Critical for Binding of Bone Morphogenetic Protein-4
2008Co-Authors: Yucheng Yao, Ani Shahbazian, Kristina I. BoströmAbstract:Arterial calcification is ubiquitous in vascular disease and is, in part, prevented by matrix Gla Protein (MGP). MGP binds calcium ions through γ-carboxylated glutamates (Gla residues) and inhibits...
Leon J. Schurgers - One of the best experts on this subject based on the ideXlab platform.
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matrix Gla Protein is an independent predictor of both intimal and medial vascular calcification in chronic kidney disease
2020Co-Authors: Armand M G Jaminon, Leon J. Schurgers, Lu Dai, Abdul Rashid Qureshi, Pieter Evenepoel, Jonaz Ripsweden, Magnus Soderberg, Anna Witasp, Hannes Olauson, Peter StenvinkelAbstract:Matrix Gla Protein (MGP) is a potent inhibitor of vascular calcification (VC) and requires carboxylation by vitamin K to exert calcification inhibition. Chronic kidney disease (CKD) patients undergo early vascular aging often involving extensive VC. The present cross-sectional study investigated the association between circulating dp-ucMGP levels, MGP expression in vascular tissue and MGP polymorphisms. In 141 CKD stage 5 patients, CAC score was significantly increased in the highest tertile of dp-ucMGP (p = 0.002), and a high medial VC score was associated with elevated dp-ucMGP levels. MGP vascular expression was associated with increased circulating dp-ucMGP and CAC scores. MGP SNP analysis revealed that patients homozygous for the C allele of the rs1800801 variant had a higher CAC score (median 15 [range 0-1312]) compared to patients carrying a T allele (median 0 [range 0-966] AU). These results indicate that plasma levels of dp-ucMGP are an independent predictor of increased VC in CKD5 patients and correlate with both higher CAC scores and degree of medial calcification. Additionally, high vascular expression of MGP was associated with higher CAC scores and plasma dp-ucMGP levels. Taken together, our results support that MGP is involved in the pathogenesis of VC.
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effect of 6 month vitamin d supplementation on plasma matrix Gla Protein in older adults
2019Co-Authors: Adriana J Van Ballegooijen, Joline W J Beulens, Leon J. Schurgers, Elisa J De Koning, Paul Lips, Natasja M Van Schoor, Marc G VervloetAbstract:Vitamin D supplementation has been widely promoted to restore 25-hydroxyvitamin D concentrations; however, experimental evidence suggests a nutrient interaction with vitamin K. We assessed the effects of 1200 IU vitamin D₃ per day versus placebo for six months on vitamin K status in a randomized, double-blind, placebo-controlled trial with participants aged 60⁻80 years with depressive symptoms and ≥1 functional limitation for a secondary analysis. Stored baseline and six-month follow-up blood samples were available for 131 participants (n = 65 placebo vs. n = 66 vitamin D supplementation). We measured dephosphorylated uncarboxylated matrix Gla Protein (MGP) (dp-ucMGP) concentrations-a marker of vitamin K deficiency. Mean age was 68 years, and 89 participants (68%) were women. Vitamin K antagonists were used by 16 participants and multivitamin supplements by 50 participants. No differences in change between intervention and placebo were found (-38.5 ± 389 vs. 4.5 ± 127 (pmol/L), p = 0.562). When excluding vitamin K antagonist users and multivitamin users, dp-ucMGP at follow-up was significantly higher in the vitamin D group (n = 40) compared to placebo (n = 30), with a difference of 92.8 (5.7, 180) pmol/L, adjusting for baseline dp-ucMGP and sex. In conclusion, vitamin D supplementation for six months did not affect vitamin K status; however, among participants without vitamin K antagonist or multivitamin use, vitamin D supplementation influenced dp-ucMGP concentrations.
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Renal matrix Gla Protein expression increases progressively with CKD and predicts renal outcome.
2018Co-Authors: Kana N. Miyata, Leon J. Schurgers, Cynthia C. Nast, Tiane Dai, Ramanath Dukkipati, Janine Lapage, Jonathan P. Troost, Matthias Kretzler, Sharon G. AdlerAbstract:Abstract Background Matrix Gla Protein (MGP) is a potent inhibitor of ectopic calcification and modulates bone morphogenesis. Little is known about MGP expression or function in kidney. Methods We investigated renal MGP expression in Sprague-Dawley rats after 5/6 nephrectomy (5/6 Nx) and in human kidney biopsies in the Nephrotic Syndrome Study Network (NEPTUNE) cohort. We analyzed associations between glomerular (n = 182) and tubulointerstitial (TI) (n = 219) MGP mRNA levels and the disease activity/histologic features in NEPTUNE patients. Additionally, uncarboxylated and carboxylated MGP (ucMGP and cMGP, respectively) were localized by immunohistochemistry and quantitated in kidney tissues of patients at different stages of CKD (n = 18). Results Renal MGP expression was increased in rats after 5/6 Nx. In NEPTUNE data, baseline estimated glomerular filtration rate (eGFR) negatively correlated with glomerular and TI MGP expression (p Conclusions Our data demonstrate that renal MGP expression is increased in human and experimental CKD, and is associated with renal outcome. Additional studies are needed to determine its mechanism of action.
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vitamin k dependent carboxylation of matrix Gla Protein a crucial switch to control ectopic mineralization
2013Co-Authors: Leon J. Schurgers, Jouni Uitto, Chris P M ReutelingspergerAbstract:Vascular mineralization has recently emerged as a risk factor for cardiovascular morbidity and mortality. Previously regarded as a passive end-stage process, vascular mineralization is currently recognized as an actively regulated process with cellular and humoral contributions. The discovery that the vitamin K-dependent matrix Gla-Protein (MGP) is a strong inhibitor of vascular calcification has propelled our mechanistic understanding of this process and opened novel avenues for diagnosis and treatment. This review focuses on molecular mechanisms of vascular mineralization involving MGP and discusses the potential for treatments and biomarkers to monitor patients at risk for vascular mineralization.
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matrix Gla Protein and alkaline phosphatase are differently modulated in human dermal fibroblasts from pxe patients and controls
2013Co-Authors: Federica Boraldi, Cees Vermeer, Leon J. Schurgers, Giulia Annovi, Tornmaso Trenti, Roberta Tiozzo, Deanna Guerra, Daniela QuaglinoAbstract:Mineralization of elastic fibers in pseudoxanthoma elasticum (PXE) has been associated with low levels of carboxylated matrix Gla Protein (MGP), most likely as a consequence of reduced vitamin K (vit K) availability. Unexpectedly, vit K supplementation does not exert beneficial effects on soft connective tissue mineralization in the PXE animal model. To understand the effects of vit K supplementation and in the attempt to interfere with pathways leading to the accumulation of calcium and phosphate within PXE-mineralized soft connective tissues, we have conducted in vitro studies on dermal fibroblasts isolated from control subjects and from PXE patients. Cells were cultured in standard conditions and in calcifying medium (CM) in the presence of vit K1 and K2, or levamisole, an alkaline phosphatase (ALP) inhibitor. Control and PXE fibroblasts were characterized by a similar dose-dependent uptake of both vit K1 and vit K2, thus promoting a significant increase of total Protein carboxylation in all cell lines. Nevertheless, MGP carboxylation remained much less in PXE fibroblasts. Interestingly, PXE fibroblasts exhibited a significantly higher ALP activity. Consistently, the mineralization process induced in vitro by a long-term culture in CM appeared unaffected by vit K, whereas it was abolished by levamisole.
Monzur Murshed - One of the best experts on this subject based on the ideXlab platform.
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matrix Gla Protein deficiency impairs nasal septum growth causing midface hypoplasia
2017Co-Authors: Juliana Marulanda, Hazem Eimar, Michelle Berkvens, Hassem Roman, Teresa Borras, Mathieu Ferron, Faleh Tamimi, Marc D Mckee, Valentin Nelea, Monzur MurshedAbstract:Abstract Genetic and environmental factors may lead to abnormal growth of the orofacial skeleton affecting the overall structure of the face. In the current study, we investigated the craniofacial abnormalities in a mouse model for Keutel syndrome, a rare genetic disease caused by loss-of-function mutations in the matrix Gla Protein (MGP) gene. Keutel syndrome patients show diffuse ectopic calcification of cartilaginous tissues and impaired midface development. Our comparative cephalometric analyses of micro-CT images revealed a severe midface hypoplasia in Mgp-/- mice. In vivo reporter studies demonstrated that the Mgp promoter is highly active at the cranial sutures, cranial base synchondroses and nasal septum. While sutures and cranial base synchondroses showed normal anatomical features, the nasal septum was found to be abnormally mineralized and shortened in Mgp-/- mice. Transgenic restoration of Mgp expression in chondrocytes fully corrected the craniofacial anomalies caused by MGP deficiency, suggesting a local role for MGP in the developing nasal septum. Although there was no upregulation of markers for hypertrophic chondrocytes, TUNEL assay showed a marked increase of apoptotic chondrocytes in the calcified nasal septum. Transmission electron microscopy confirmed unusual mineral deposits in the septal extracellular matrix (ECM) of the mutant mice. Of note, systemic reduction of inorganic phosphate level was sufficient to prevent nasal septum mineralization in Mgp-/-;Hyp compound mutants. Our work provides evidence that modulation of local and systemic factors regulating ECM mineralization can be possible therapeutic strategies to prevent ectopic cartilage calcification and some forms of congenital craniofacial anomalies in humans.
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matrix Gla Protein deficiency impairs nasal septum growth causing midface hypoplasia
2017Co-Authors: Juliana Marulanda, Hazem Eimar, Michelle Berkvens, Hassem Roman, Teresa Borras, Mathieu Ferron, Faleh Tamimi, Marc D Mckee, Valentin Nelea, Monzur MurshedAbstract:Genetic and environmental factors may lead to abnormal growth of the orofacial skeleton, affecting the overall structure of the face. In this study, we investigated the craniofacial abnormalities in a mouse model for Keutel syndrome, a rare genetic disease caused by loss-of-function mutations in the matrix Gla Protein (MGP) gene. Keutel syndrome patients show diffuse ectopic calcification of cartilaginous tissues and impaired midface development. Our comparative cephalometric analyses of micro-computed tomography images revealed a severe midface hypoplasia in Mgp−/− mice. In vivo reporter studies demonstrated that the Mgp promoter is highly active at the cranial sutures, cranial base synchondroses, and nasal septum. Interestingly, the cranial sutures of the mutant mice showed normal anatomical features. Although we observed a mild increase in mineralization of the spheno-occipital synchondrosis, it did not reduce the relative length of the cranial base in comparison with total skull length. Contrary to this, we found the nasal septum to be abnormally mineralized and shortened in Mgp−/− mice. Transgenic restoration of Mgp expression in chondrocytes fully corrected the craniofacial anomalies caused by MGP deficiency, suggesting a local role for MGP in the developing nasal septum. Although there was no up-regulation of markers for hypertrophic chondrocytes, a TUNEL assay showed a marked increase in apoptotic chondrocytes in the calcified nasal septum. Transmission electron microscopy confirmed unusual mineral deposits in the septal extracellular matrix of the mutant mice. Of note, the systemic reduction of the inorganic phosphate level was sufficient to prevent abnormal mineralization of the nasal septum in Mgp−/−;Hyp compound mutants. Our work provides evidence that modulation of local and systemic factors regulating extracellular matrix mineralization can be possible therapeutic strategies to prevent ectopic cartilage calcification and some forms of congenital craniofacial anomalies in humans.
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osteopontin upregulation and polymerization by transglutaminase 2 in calcified arteries of matrix Gla Protein deficient mice
2007Co-Authors: Mari T. Kaartinen, Monzur Murshed, Gerard Karsenty, Marc D MckeeAbstract:Matrix Gla Protein (MGP) is a potent inhibitor of soft tissue calcification, and Mgp gene deletion in mice results in arterial calcification. Our aim was to examine osteopontin (OPN) expression and localization, and posttranslational processing of OPN by the crosslinking enzyme transglutaminase 2 (TG2), in the calcified aorta of Mgp-deficient (Mgp(-/-)) mice. Using immunohistochemistry and light and electron microscopy, we report that following mineralization occurring in the arterial media of Mgp(-/-) aortas, OPN is upregulated and accumulates at the surface of the calcified elastic lamellae. Macrophages were observed in direct contact with this OPN-rich layer. Western blot analysis of extracted Mgp(-/-) aortas revealed that the majority of the OPN was in high molecular mass Protein complexes, indicating modification by a crosslinking enzyme. Consistent with this observation, TG2 expression and gamma-glutamyl-epsilon-lysyl crosslink levels were also increased in Mgp(-/-) aortas. In addition to the mineral-inhibiting actions of OPN, and based on data linking OPN and TG2 with cell adhesion in various cell types including monocytes and macrophages, we propose that TG2 interactions with OPN lead to Protein polymerization that facilitates macrophage adhesion to the calcified elastic lamellae to promote clearance of the ectopic mineral deposits.
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Cartilage Formation and Calcification in Arteries of Mice Lacking Matrix Gla Protein
2003Co-Authors: Sherif El‐maadawy, Monzur Murshed, Gerard Karsenty, Mari T. Kaartinen, Thorsten Schinke, Marc D MckeeAbstract:Matrix Gla Protein (MGP/Mgp) is a Protein expressed predominantly by vascular smooth muscle cells (VSMCs) and by chondrocytes. Transgenic mice lacking Mgp die 1-3 months after birth due to calcification of elastic fibers and rupture of large elastic arteries such as the aorta. Here, we report on cartilage formation that commonly occurs in calcified arteries of Mgp-/- mice. Using histology, von Kossa staining, immunohistochemistry, and Western blotting, together with examination of cellular markers for VSMCs and extracellular matrix markers for cartilage, we provide evidence for cell transformation from VSMC to chondrocyte in the arterial media in the absence of Mgp. At 2 weeks of age in the aorta of Mgp-/- mice, VSMCs lose immunostaining for smooth muscle alpha-actin concomitant with the appearance of cartilage molecules as shown by immunohistochemical staining and Western blotting for aggrecan, link Protein, and type II collagen. These data provide evidence that the absence of Mgp, and/or calcification of the ECM, in the arterial media can trigger chondrocyte differentiation and cartilage formation in blood vessels.
Yucheng Yao - One of the best experts on this subject based on the ideXlab platform.
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Matrix Gla Protein regulates differentiation of endothelial cells derived from mouse embryonic stem cells.
2015Co-Authors: Jiayi Yao, Kristina I. Boström, Pierre J. Guihard, Ana M. Blazquez-medela, Yina Guo, Ting Liu, Yucheng YaoAbstract:Matrix Gla Protein (MGP) is an antagonist of bone morphogenetic Proteins and expressed in vascular endothelial cells. Lack of MGP causes vascular abnormalities in multiple organs in mice. The objective of this study is to define the role of MGP in early endothelial differentiation. We find that expression of endothelial markers is highly induced in Mgp null organs, which, in wild type, contain high MGP expression. Furthermore, Mgp null embryonic stem cells express higher levels of endothelial markers than wild-type controls and an abnormal temporal pattern of expression. We also find that the Mgp-deficient endothelial cells adopt characteristics of mesenchymal stem cells. We conclude that loss of MGP causes dysregulation of early endothelial differentiation.
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reducing jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla Protein deficiency
2013Co-Authors: Yucheng Yao, Medet Jumabay, Jiayi Yao, Pierre J. Guihard, Melina Radparvar, Ana M Blazquezmedela, Kristina I. BoströmAbstract:Cerebral arteriovenous malformations (AVMs) are common vascular malformations, which may result in hemorrhagic strokes and neurological deficits. Bone morphogenetic Protein (BMP) and Notch signaling are both involved in the development of cerebral AVMs, but the cross-talk between the two signaling pathways is poorly understood. Here, we show that deficiency of matrix Gla Protein (MGP), a BMP inhibitor, causes induction of Notch ligands, dysregulation of endothelial differentiation, and the development of cerebral AVMs in MGP null (Mgp−/−) mice. Increased BMP activity due to the lack of MGP induces expression of the activin receptor-like kinase 1, a BMP type I receptor, in cerebrovascular endothelium. Subsequent activation of activin receptor-like kinase 1 enhances expression of Notch ligands Jagged 1 and 2, which increases Notch activity and alters the expression of Ephrin B2 and Ephrin receptor B4, arterial and venous endothelial markers, respectively. Reducing the expression of Jagged 1 and 2 in the Mgp−/− mice by crossing them with Jagged 1 or 2 deficient mice reduces Notch activity, normalizes endothelial differentiation, and prevents cerebral AVMs, but not pulmonary or renal AVMs. Our results suggest that Notch signaling mediates and can modulate changes in BMP signaling that lead to cerebral AVMs.
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Matrix Gla Protein deficiency causes arteriovenous malformations in mice
2011Co-Authors: Yucheng Yao, Medet Jumabay, Anthony Wang, Kristina I. BoströmAbstract:Arteriovenous malformations (AVMs) in organs, such as the lungs, intestine, and brain, are characteristic of hereditary hemorrhagic telangiectasia (HHT), a disease caused by mutations in activin-like kinase receptor 1 (ALK1), which is an essential receptor in angiogenesis, or endoglin. Matrix Gla Protein (MGP) is an antagonist of BMPs that is highly expressed in lungs and kidneys and is regulated by ALK1. The objective of this study was to determine the role of MGP in the vasculature of the lungs and kidneys. We found that Mgp gene deletion in mice caused striking AVMs in lungs and kidneys, where overall small organ size contrasted with greatly increased vascularization. Mechanistically, MGP deficiency increased BMP activity in lungs. In cultured lung epithelial cells, BMP-4 induced VEGF expression through induction of ALK1, ALK2, and ALK5. The VEGF secretion induced by BMP-4 in Mgp-/- epithelial cells stimulated proliferation of ECs. However, BMP-4 inhibited proliferation of lung epithelial cells, consistent with the increase in pulmonary vasculature at the expense of lung tissue in the Mgp-null mice. Similarly, BMP signaling and VEGF expression were increased in Mgp-/- mouse kidneys. We therefore conclude that Mgp gene deletion is what we believe to be a previously unidentified cause of AVMs. Because lack of MGP also causes arterial calcification, our findings demonstrate that the same gene defect has drastically different effects on distinct vascular beds.
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heat shock Protein 70 enhances vascular bone morphogenetic Protein 4 signaling by binding matrix Gla Protein
2009Co-Authors: Yucheng Yao, Andrew D Watson, Kristina I. BoströmAbstract:Rationale: Matrix Gla Protein (MGP) is a calcification inhibitor, which binds and inhibits bone morphogenetic Protein (BMP)-2 and -4. Objective: The objective was to determine whether MGP also binds other Proteins, which could interfere with its function. Methods and Results: We transfected bovine aortic endothelial cells with N-terminally FLAG-tagged MGP and used immunoprecipitation and liquid chromatographic–tandem mass spectrometric analysis to identify MGP-binding Proteins. Heat shock Protein (HSP)70, a stress-induced Protein expressed in atherosclerotic lesions and soluble in serum, was identified as a novel MGP-binding Protein. The interaction between MGP and HSP70 was confirmed by coimmunoprecipitation and chemical crosslinking, and blocked the interaction between MGP and BMP-4. In endothelial cells, HSP70 enhanced BMP-4–induced proliferation and tube formation, and in calcifying vascular cells, HSP70 enhanced BMP-induced calcium deposition. In addition, HSP70 mediated the procalcific effect of interleukin-6 on calcifying vascular cells. In apolipoProtein E–null mice, a model for atherosclerosis, levels of BMP-4, HSP70, MGP, and interleukin-6 were elevated in the aortic wall. Levels of BMP-4, HSP70, and interleukin-6 were also elevated in serum, and anti-HSP70 antibodies diminished its procalcific effect on calcifying vascular cells. Conclusion: HSP70 binds MGP and enhances BMP activity, thereby functioning as a potential link between cellular stress, inflammation, and BMP signaling.
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Proline and γ-Carboxylated Glutamate Residues in Matrix Gla Protein Are Critical for Binding of Bone Morphogenetic Protein-4
2008Co-Authors: Yucheng Yao, Ani Shahbazian, Kristina I. BoströmAbstract:Arterial calcification is ubiquitous in vascular disease and is, in part, prevented by matrix Gla Protein (MGP). MGP binds calcium ions through γ-carboxylated glutamates (Gla residues) and inhibits...