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Cees Vermeer - One of the best experts on this subject based on the ideXlab platform.

  • Aldosterone, inactive Matrix Gla-Protein, and large artery stiffness in hypertension.
    Journal of the American Society of Hypertension : JASH, 2018
    Co-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 Vermeer
    Abstract:

    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

  • vitamin k dependent carboxylation of Matrix Gla Protein influences the risk of calciphylaxis
    Journal of The American Society of Nephrology, 2017
    Co-Authors: Sagar U Nigwekar, Cees Vermeer, Sarah L. Booth, D Bloch, Rosalynn M Nazarian, Dihua Xu, Ravi Thadhani, Rajeev Malhotra
    Abstract:

    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.

  • Plasma Desphospho-Uncarboxylated Matrix Gla Protein as a Marker of Kidney Damage and Cardiovascular Risk in Advanced Stage of Chronic Kidney Disease.
    Kidney & blood pressure research, 2016
    Co-Authors: Ilona Kurnatowska, Cees Vermeer, Piotr Grzelak, Anna Masajtis-zagajewska, Magdalena Kaczmarska, Ludomir Stefańczyk, Katarzyna Maresz, Michał Nowicki
    Abstract:

    Background/Aims: Desphospho-uncarboxylated Matrix Gla Protein (dp-ucMGP) is formed as a result of vitamin K insufficiency. The aim of this study was to investigat

  • circulating nonphosphorylated carboxylated Matrix Gla Protein predicts survival in esrd
    Journal of The American Society of Nephrology, 2011
    Co-Authors: Georg Schlieper, Elke J. Magdeleyns, Ralf Westenfeld, Thilo Kruger, Ellen C Cranenburg, Vincent Brandenburg, Zivka Djuric, Tatjana Damjanovic, Markus Ketteler, Cees Vermeer
    Abstract:

    The mechanisms for vascular calcification and its associated cardiovascular mortality in patients with ESRD are not completely understood. Dialysis patients exhibit profound vitamin K deficiency, which may impair carboxylation of the calcification inhibitor Matrix Gla Protein (MGP). Here, we tested whether distinct circulating inactive vitamin K–dependent Proteins associate with all-cause or cardiovascular mortality. We observed higher levels of both desphospho-uncarboxylated MGP (dp-ucMGP) and desphospho-carboxylated MGP (dp-cMGP) among 188 hemodialysis patients compared with 98 age-matched subjects with normal renal function. Levels of dp-ucMGP correlated with those of Protein induced by vitamin K absence II (PIVKA-II; r = 0.62, P < 0.0001). We found increased PIVKA-II levels in 121 (64%) dialysis patients, indicating pronounced vitamin K deficiency. Kaplan-Meier analysis showed that patients with low levels of dp-cMGP had an increased risk for all-cause and cardiovascular mortality. Multivariable Cox regression confirmed that low levels of dp-cMGP increase mortality risk (all-cause: HR, 2.2; 95% CI, 1.1 to 4.3; cardiovascular: HR, 2.7; 95% CI, 1.2 to 6.2). Furthermore, patients with higher vascular calcification scores showed lower levels of dp-cMGP. In 17 hemodialysis patients, daily supplementation with vitamin K2 for 6 weeks reduced dp-ucMGP levels by 27% (P = 0.003) but did not affect dp-cMGP levels. In conclusion, the majority of dialysis patients exhibit pronounced vitamin K deficiency. Lower levels of circulating dp-cMGP may serve as a predictor of mortality in dialysis patients. Whether vitamin K supplementation improves outcomes requires further study.

  • Undercarboxylated Matrix Gla Protein is associated with indices of heart failure and mortality in symptomatic aortic stenosis.
    Journal of internal medicine, 2010
    Co-Authors: Thor Ueland, Cees Vermeer, Lars Gullestad, Christen P. Dahl, P. Aukrust, S. Aakhus, Ole Geir Solberg, Leon J. Schurgers
    Abstract:

    .  Ueland T, Gullestad L, Dahl CP, Aukrust P, Aakhus S, Solberg OG, Vermeer C, Schurgers LJ (Research Institute for Internal Medicine, University of Oslo, Oslo; University of Oslo, Oslo, Norway; and VitaK & Cardiovascular Research Institute CARIM (CV, LS), Maastricht University, Maastricht, The Netherlands) Undercarboxylated Matrix Gla Protein is associated with indices of heart failure and mortality in symptomatic aortic stenosis. J Intern Med 2010; 268: 483–492. Objective.  Matrix Gla Protein (MGP) is a calcification inhibitor and alterations in circulating MGP have been observed in different populations characterized by vascular calcification. We hypothesized that patients with calcific valvular aortic stenosis (AS) would have dysregulated circulating MGP levels. Design and subjects.  We examined plasma levels of nonphosphorylated carboxylated and undercarboxylated MGP (dp-cMGP and dp-ucMGP, respectively) in 147 patients with symptomatic severe AS and in matched healthy controls. Main outcome measures.  We further investigated the relationship between MGP levels and aortic pressure gradients and valve area by echocardiography and measures of heart failure. Finally, we assessed the prognostic value of elevated plasma dp-ucMGP level in relation to all-cause mortality in patients with AS. Results.  We found markedly enhanced plasma levels of dp-cMGP and in particular of dp-ucMGP in patients with symptomatic AS. Although only weak correlations were found with the degree of AS, circulating dp-ucMGP was associated with cardiac function and long-term mortality in multivariate analysis. Conclusions.  A dysregulated MGP system may have a role in the development of left ventricular dysfunction in patients with symptomatic AS.

Leon J. Schurgers - One of the best experts on this subject based on the ideXlab platform.

  • Renal Matrix Gla Protein expression increases progressively with CKD and predicts renal outcome.
    Experimental and molecular pathology, 2018
    Co-Authors: Kana N. Miyata, Leon J. Schurgers, Cynthia C. Nast, Tiane Dai, Ramanath Dukkipati, Janine Lapage, Jonathan P. Troost, Matthias Kretzler, Sharon G. Adler
    Abstract:

    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.

  • vitamin k dependent carboxylation of Matrix Gla Protein a crucial switch to control ectopic mineralization
    Trends in Molecular Medicine, 2013
    Co-Authors: Leon J. Schurgers, Jouni Uitto, Chris P M Reutelingsperger
    Abstract:

    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.

  • Undercarboxylated Matrix Gla Protein is associated with indices of heart failure and mortality in symptomatic aortic stenosis.
    Journal of internal medicine, 2010
    Co-Authors: Thor Ueland, Cees Vermeer, Lars Gullestad, Christen P. Dahl, P. Aukrust, S. Aakhus, Ole Geir Solberg, Leon J. Schurgers
    Abstract:

    .  Ueland T, Gullestad L, Dahl CP, Aukrust P, Aakhus S, Solberg OG, Vermeer C, Schurgers LJ (Research Institute for Internal Medicine, University of Oslo, Oslo; University of Oslo, Oslo, Norway; and VitaK & Cardiovascular Research Institute CARIM (CV, LS), Maastricht University, Maastricht, The Netherlands) Undercarboxylated Matrix Gla Protein is associated with indices of heart failure and mortality in symptomatic aortic stenosis. J Intern Med 2010; 268: 483–492. Objective.  Matrix Gla Protein (MGP) is a calcification inhibitor and alterations in circulating MGP have been observed in different populations characterized by vascular calcification. We hypothesized that patients with calcific valvular aortic stenosis (AS) would have dysregulated circulating MGP levels. Design and subjects.  We examined plasma levels of nonphosphorylated carboxylated and undercarboxylated MGP (dp-cMGP and dp-ucMGP, respectively) in 147 patients with symptomatic severe AS and in matched healthy controls. Main outcome measures.  We further investigated the relationship between MGP levels and aortic pressure gradients and valve area by echocardiography and measures of heart failure. Finally, we assessed the prognostic value of elevated plasma dp-ucMGP level in relation to all-cause mortality in patients with AS. Results.  We found markedly enhanced plasma levels of dp-cMGP and in particular of dp-ucMGP in patients with symptomatic AS. Although only weak correlations were found with the degree of AS, circulating dp-ucMGP was associated with cardiac function and long-term mortality in multivariate analysis. Conclusions.  A dysregulated MGP system may have a role in the development of left ventricular dysfunction in patients with symptomatic AS.

  • calcium scores and Matrix Gla Protein levels association with vitamin k status
    European Journal of Clinical Investigation, 2010
    Co-Authors: Roger J. M. W. Rennenberg, Cees Vermeer, Leon J. Schurgers, Peter W. De Leeuw, Alphons G.h. Kessels, Jos M. A. Van Engelshoven, Gerrit J. Kemerink, Abraham A. Kroon
    Abstract:

    Eur J Clin Invest 2010; 40 (4): 344–349 Abstract Background  Vascular calcification in humans is associated with an increased cardiovascular risk. Carboxylated Matrix Gla Protein (cMGP) inhibits vascular calcification. Vitamin K is an essential cofactor for the activation of uncarboxylated Matrix Gla Protein (ucMGP). It has been suggested that patients on long-term treatment with vitamin K antagonists develop aortic valve calcifications because of lower levels of circulating MGP. We therefore hypothesized that arterial calcification and a low vitamin K status are associated with ucMGP. To that aim, we measured arterial calcium scores, the osteocalcin ratio (OCR), as a proxy for vitamin K status, and ucMGP. Materials and methods  In 36 hypertensive patients, we determined the Agatston score with computer tomography scans of the abdominal aorta, carotid and coronary arteries. The total calcium score was calculated as the sum of the separate Z-scores. Results  The total calcium Z-score was significantly correlated to age (r = 0·683, P < 0·001), smoking (r = 0·372, P = 0·026), total cholesterol (r = 0·353, P = 0·034), LDL cholesterol (r = 0·490, P = 0·003), triglycerides (r = 0·506, P = 0·002), fasting glucose (r = 0·454, P = 0·005), systolic blood pressure (r = 0·363, P = 0·029) and pulse pressure (r = 0·685, P < 0·001). In multivariate regression analyses, OCR and total calcium score were significantly associated with ucMGP. Conclusions  We found a positive association of total arterial calcium score and a high OCR (reflecting low vitamin K status) with ucMGP serum levels. This warrants further studies to explore the pathophysiological background of this phenomenon.

  • Calcium scores and Matrix Gla Protein levels: association with vitamin K status.
    European journal of clinical investigation, 2010
    Co-Authors: Roger J. M. W. Rennenberg, Cees Vermeer, Leon J. Schurgers, Peter W. De Leeuw, Alphons G.h. Kessels, Jos M. A. Van Engelshoven, Gerrit J. Kemerink, Abraham A. Kroon
    Abstract:

    Eur J Clin Invest 2010; 40 (4): 344–349 Abstract Background  Vascular calcification in humans is associated with an increased cardiovascular risk. Carboxylated Matrix Gla Protein (cMGP) inhibits vascular calcification. Vitamin K is an essential cofactor for the activation of uncarboxylated Matrix Gla Protein (ucMGP). It has been suggested that patients on long-term treatment with vitamin K antagonists develop aortic valve calcifications because of lower levels of circulating MGP. We therefore hypothesized that arterial calcification and a low vitamin K status are associated with ucMGP. To that aim, we measured arterial calcium scores, the osteocalcin ratio (OCR), as a proxy for vitamin K status, and ucMGP. Materials and methods  In 36 hypertensive patients, we determined the Agatston score with computer tomography scans of the abdominal aorta, carotid and coronary arteries. The total calcium score was calculated as the sum of the separate Z-scores. Results  The total calcium Z-score was significantly correlated to age (r = 0·683, P 

Jouni Uitto - One of the best experts on this subject based on the ideXlab platform.

  • vitamin k dependent carboxylation of Matrix Gla Protein a crucial switch to control ectopic mineralization
    Trends in Molecular Medicine, 2013
    Co-Authors: Leon J. Schurgers, Jouni Uitto, Chris P M Reutelingsperger
    Abstract:

    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.

  • pseudoxanthoma elasticum reduced γ glutamyl carboxylation of Matrix Gla Protein in a mouse model abcc6
    Biochemical and Biophysical Research Communications, 2007
    Co-Authors: Qiujie Jiang, Leon J. Schurgers, Jouni Uitto
    Abstract:

    Pseudoxanthoma elasticum (PXE), a heritable multi-system disorder manifesting with ectopic mineralization of soft connective tissues, is caused by mutations in the ABCC6/MRP6 gene/Protein system, but the mechanisms how the ABCC6 mutations lead to aberrant mineralization are currently unknown. In this study, we utilized a transgenic mouse model, Abcc6−/−, to examine the mineralization processes. We focused on Matrix Gla Protein (MGP) which has been shown to be critical, when activated by γ-carboxylation of glutamyl residues, for prevention of unwanted mineralization. The concentration of MGP in the serum of Abcc6−/− mice was significantly reduced when compared to wild-type controls (p < 0.004). More importantly, MGP isolated from the liver of Abcc6−/− mice was largely under-carboxylated and therefore possesses no activity. Finally, examination of the Abcc6−/− mice revealed association of total and under-carboxylated forms of MGP with ectopic mineralization while the γ-carboxylated form was essentially absent. These results suggest that MGP in Abcc6−/− mice is largely in inactive form and is unable to prevent the unwanted mineralization of connective tissues in PXE.

  • Pseudoxanthoma elasticum: Reduced γ-glutamyl carboxylation of Matrix Gla Protein in a mouse model (Abcc6−/−)
    Biochemical and biophysical research communications, 2007
    Co-Authors: Qiujie Jiang, Leon J. Schurgers, Jouni Uitto
    Abstract:

    Pseudoxanthoma elasticum (PXE), a heritable multi-system disorder manifesting with ectopic mineralization of soft connective tissues, is caused by mutations in the ABCC6/MRP6 gene/Protein system, but the mechanisms how the ABCC6 mutations lead to aberrant mineralization are currently unknown. In this study, we utilized a transgenic mouse model, Abcc6−/−, to examine the mineralization processes. We focused on Matrix Gla Protein (MGP) which has been shown to be critical, when activated by γ-carboxylation of glutamyl residues, for prevention of unwanted mineralization. The concentration of MGP in the serum of Abcc6−/− mice was significantly reduced when compared to wild-type controls (p 

Qiujie Jiang - One of the best experts on this subject based on the ideXlab platform.

  • pseudoxanthoma elasticum reduced γ glutamyl carboxylation of Matrix Gla Protein in a mouse model abcc6
    Biochemical and Biophysical Research Communications, 2007
    Co-Authors: Qiujie Jiang, Leon J. Schurgers, Jouni Uitto
    Abstract:

    Pseudoxanthoma elasticum (PXE), a heritable multi-system disorder manifesting with ectopic mineralization of soft connective tissues, is caused by mutations in the ABCC6/MRP6 gene/Protein system, but the mechanisms how the ABCC6 mutations lead to aberrant mineralization are currently unknown. In this study, we utilized a transgenic mouse model, Abcc6−/−, to examine the mineralization processes. We focused on Matrix Gla Protein (MGP) which has been shown to be critical, when activated by γ-carboxylation of glutamyl residues, for prevention of unwanted mineralization. The concentration of MGP in the serum of Abcc6−/− mice was significantly reduced when compared to wild-type controls (p < 0.004). More importantly, MGP isolated from the liver of Abcc6−/− mice was largely under-carboxylated and therefore possesses no activity. Finally, examination of the Abcc6−/− mice revealed association of total and under-carboxylated forms of MGP with ectopic mineralization while the γ-carboxylated form was essentially absent. These results suggest that MGP in Abcc6−/− mice is largely in inactive form and is unable to prevent the unwanted mineralization of connective tissues in PXE.

  • Pseudoxanthoma elasticum: Reduced γ-glutamyl carboxylation of Matrix Gla Protein in a mouse model (Abcc6−/−)
    Biochemical and biophysical research communications, 2007
    Co-Authors: Qiujie Jiang, Leon J. Schurgers, Jouni Uitto
    Abstract:

    Pseudoxanthoma elasticum (PXE), a heritable multi-system disorder manifesting with ectopic mineralization of soft connective tissues, is caused by mutations in the ABCC6/MRP6 gene/Protein system, but the mechanisms how the ABCC6 mutations lead to aberrant mineralization are currently unknown. In this study, we utilized a transgenic mouse model, Abcc6−/−, to examine the mineralization processes. We focused on Matrix Gla Protein (MGP) which has been shown to be critical, when activated by γ-carboxylation of glutamyl residues, for prevention of unwanted mineralization. The concentration of MGP in the serum of Abcc6−/− mice was significantly reduced when compared to wild-type controls (p 

Kristina I. Boström - One of the best experts on this subject based on the ideXlab platform.

  • Matrix Gla Protein regulates differentiation of endothelial cells derived from mouse embryonic stem cells.
    Angiogenesis, 2015
    Co-Authors: Jiayi Yao, Kristina I. Boström, Pierre J. Guihard, Ana M. Blazquez-medela, Yina Guo, Ting Liu, Yucheng Yao
    Abstract:

    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.

  • Matrix Gla Protein deficiency causes arteriovenous malformations in mice
    Journal of Clinical Investigation, 2011
    Co-Authors: Yucheng Yao, Medet Jumabay, Anthony Wang, Kristina I. Boström
    Abstract:

    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.

  • Proline and γ-Carboxylated Glutamate Residues in Matrix Gla Protein Are Critical for Binding of Bone Morphogenetic Protein-4
    Circulation research, 2008
    Co-Authors: Yucheng Yao, Ani Shahbazian, Kristina I. Boström
    Abstract:

    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...

  • Matrix Gla Protein, an Inhibitory Morphogen in Pulmonary Vascular Development
    The Journal of biological chemistry, 2007
    Co-Authors: Yucheng Yao, Sarah A. Nowak, Arik Yochelis, Alan Garfinkel, Kristina I. Boström
    Abstract:

    Deficiency of Matrix Gla Protein (MGP), an inhibitor of bone morphogenetic Protein (BMP)-2/4, is known to cause arterial calcification and peripheral pulmonary artery stenosis. Yet the vascular role of MGP remains poorly understood. To further investigate MGP, we created a new MGP transgenic mouse model with high expression of the transgene in the lungs. The excess MGP led to a disruption of the pulmonary pattern of BMP-4, and resulted in significant morphological defects in the pulmonary artery tree. Specifically, the vascular branching pattern lacked characteristic side branching, whereas control lungs had extensive side branching accounting for as much as 40% of the vascular endothelium. The vascular changes could be explained by a dramatic reduction of phosphorylated SMAD1/ 5/8 in the alveolar epithelium, and in epithelial expression of the activin-like kinase receptor 1 and vascular endothelial growth factor, both critical in vascular formation. Abnormalities were also found in the terminal airways and in lung cell differentiation; high levels of surfactant Protein-B were distributed in an abnormal pattern suggesting lost coordination between vasculature and airways. Ex vivo, lung cells from MGP transgenic mice showed higher proliferation, in particular surfactant Protein B-expressing cells, and conditioned medium from these cells poorly supported in vitro angiogenesis compared with normal lung cells. The vascular branching defect can be mechanistically explained by a computational model based on activator/inhibitor reaction-diffusion dynamics, where BMP-4 and MGP are considered as an activating and inhibitory morphogen, respectively, suggesting that morphogen interactions are important for vascular branching.

  • Matrix Gla Protein, a regulatory Protein for bone morphogenetic Protein-2.
    The Journal of biological chemistry, 2001
    Co-Authors: Amina F. Zebboudj, Minori Imura, Kristina I. Boström
    Abstract:

    Matrix Gla Protein (MGP) has been identified as a calcification inhibitor in cartilage and vasculature. Part of this effect may be attributed to its influence on osteoinductive activity of bone morphogenetic Protein-2 (BMP-2). To detect binding between MGP and BMP-2, we performed immunoprecipitation using MGP and BMP-2 tagged with FLAG and c-Myc. The results showed co-precipitation of BMP-2 with MGP. To quantify the effect of MGP on BMP-2 activity, we assayed for alkaline phosphatase activity and showed a dose-dependent effect. Low levels of MGP relative to BMP-2 ( 15-fold excess), however, resulted in pronounced enhancement of the osteoinductive effect of BMP-2. Cross-linking studies showed that inhibitory levels of MGP abolished BMP-2 receptor binding. Immunoblotting showed a corresponding decrease in activation of Smad1, part of the BMP signaling system. Enhancing levels of MGP resulted in increased Smad1 activation. To determine the cellular localization of BMP-2 in the presence of MGP, binding assays were performed on whole cells and cell-synthesized Matrix. Inhibitory levels of MGP yielded increased Matrix binding of BMP-2, suggesting that MGP inhibits BMP-2 in part via Matrix association. These results suggest that MGP is a BMP-2 regulatory Protein.