Controlling matrix formation and cross-linking by hypoxia in cardiovascualr tissue engineering

M.A.A. Vlimmeren, van, A. Driessen - Mol, W.J.T. Broek, van den, C.V.C. Bouten, F.P.T. Baaijens

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Abstract

In vivo functionality of cardiovascular tissue engineered constructs requires in vitro control of tissue development to obtain a well developed extracellular matrix (ECM). We hypothesize that ECM formation and maturation is stimulated by culturing at low oxygen concentrations. Gene expression levels of monolayers of human vascular-derived myofibroblasts, exposed to 7, 4, 2, 1, and 0.5% O2 (n = 9 per group) for 24 h, were measured for vascular endothelial growth factor (VEGF), procollagen 1(I) and 1(III), elastin, and cross-link enzymes lysyl oxidase (LOX) and lysyl hydroxylase 2 (LH2). After 4 days of exposure to 7, 2, and 0.5% O2 (n = 3 per group), protein synthesis was evaluated. All analyses were compared with control cultures at 21% O2. Human myofibroblasts turned to hypoxia-driven gene expression, indicated by VEGF expression, at oxygen concentrations of 4% and lower. Gene expression levels of procollagen 1(I) and 1(III) increased to 138 ± 26 and 143 ± 19%, respectively, for all oxygen concentrations below 4%. At 2% O2, LH2 and LOX gene expression levels were higher than control cultures (340 ± 53 and 136 ± 29%, respectively), and these levels increased even further with decreasing oxygen concentrations (611 ± 176 and 228 ± 45%, respectively, at 0.5% O2). Elastin gene expression levels remained unaffected. Collagen synthesis and LH2 protein levels increased at oxygen concentrations of 2% and lower. Oxygen concentrations below 4% induce enhanced ECM production by human myofibroblasts. Implementation of these results in cardiovascular tissue engineering approaches enables in vitro control of tissue development.
Original languageEnglish
Pages (from-to)1483-1491
JournalJournal of Applied Physiology
Volume109
Issue number5
DOIs
Publication statusPublished - 2010

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Tissue Engineering
2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine
Oxygen
Myofibroblasts
Gene Expression
Protein-Lysine 6-Oxidase
Extracellular Matrix
Procollagen
Elastin
Vascular Endothelial Growth Factor A
Blood Vessels
Hypoxia
Proteins
Enzymes

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Vlimmeren, van, M.A.A. ; Driessen - Mol, A. ; Broek, van den, W.J.T. ; Bouten, C.V.C. ; Baaijens, F.P.T. / Controlling matrix formation and cross-linking by hypoxia in cardiovascualr tissue engineering. In: Journal of Applied Physiology. 2010 ; Vol. 109, No. 5. pp. 1483-1491.
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abstract = "In vivo functionality of cardiovascular tissue engineered constructs requires in vitro control of tissue development to obtain a well developed extracellular matrix (ECM). We hypothesize that ECM formation and maturation is stimulated by culturing at low oxygen concentrations. Gene expression levels of monolayers of human vascular-derived myofibroblasts, exposed to 7, 4, 2, 1, and 0.5{\%} O2 (n = 9 per group) for 24 h, were measured for vascular endothelial growth factor (VEGF), procollagen 1(I) and 1(III), elastin, and cross-link enzymes lysyl oxidase (LOX) and lysyl hydroxylase 2 (LH2). After 4 days of exposure to 7, 2, and 0.5{\%} O2 (n = 3 per group), protein synthesis was evaluated. All analyses were compared with control cultures at 21{\%} O2. Human myofibroblasts turned to hypoxia-driven gene expression, indicated by VEGF expression, at oxygen concentrations of 4{\%} and lower. Gene expression levels of procollagen 1(I) and 1(III) increased to 138 ± 26 and 143 ± 19{\%}, respectively, for all oxygen concentrations below 4{\%}. At 2{\%} O2, LH2 and LOX gene expression levels were higher than control cultures (340 ± 53 and 136 ± 29{\%}, respectively), and these levels increased even further with decreasing oxygen concentrations (611 ± 176 and 228 ± 45{\%}, respectively, at 0.5{\%} O2). Elastin gene expression levels remained unaffected. Collagen synthesis and LH2 protein levels increased at oxygen concentrations of 2{\%} and lower. Oxygen concentrations below 4{\%} induce enhanced ECM production by human myofibroblasts. Implementation of these results in cardiovascular tissue engineering approaches enables in vitro control of tissue development.",
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Controlling matrix formation and cross-linking by hypoxia in cardiovascualr tissue engineering. / Vlimmeren, van, M.A.A.; Driessen - Mol, A.; Broek, van den, W.J.T.; Bouten, C.V.C.; Baaijens, F.P.T.

In: Journal of Applied Physiology, Vol. 109, No. 5, 2010, p. 1483-1491.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - Vlimmeren, van, M.A.A.

AU - Driessen - Mol, A.

AU - Broek, van den, W.J.T.

AU - Bouten, C.V.C.

AU - Baaijens, F.P.T.

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AB - In vivo functionality of cardiovascular tissue engineered constructs requires in vitro control of tissue development to obtain a well developed extracellular matrix (ECM). We hypothesize that ECM formation and maturation is stimulated by culturing at low oxygen concentrations. Gene expression levels of monolayers of human vascular-derived myofibroblasts, exposed to 7, 4, 2, 1, and 0.5% O2 (n = 9 per group) for 24 h, were measured for vascular endothelial growth factor (VEGF), procollagen 1(I) and 1(III), elastin, and cross-link enzymes lysyl oxidase (LOX) and lysyl hydroxylase 2 (LH2). After 4 days of exposure to 7, 2, and 0.5% O2 (n = 3 per group), protein synthesis was evaluated. All analyses were compared with control cultures at 21% O2. Human myofibroblasts turned to hypoxia-driven gene expression, indicated by VEGF expression, at oxygen concentrations of 4% and lower. Gene expression levels of procollagen 1(I) and 1(III) increased to 138 ± 26 and 143 ± 19%, respectively, for all oxygen concentrations below 4%. At 2% O2, LH2 and LOX gene expression levels were higher than control cultures (340 ± 53 and 136 ± 29%, respectively), and these levels increased even further with decreasing oxygen concentrations (611 ± 176 and 228 ± 45%, respectively, at 0.5% O2). Elastin gene expression levels remained unaffected. Collagen synthesis and LH2 protein levels increased at oxygen concentrations of 2% and lower. Oxygen concentrations below 4% induce enhanced ECM production by human myofibroblasts. Implementation of these results in cardiovascular tissue engineering approaches enables in vitro control of tissue development.

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JO - Journal of Applied Physiology

JF - Journal of Applied Physiology

SN - 8750-7587

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