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Effects of the HDAC inhibitor valproic acid on human pericytes in vitro
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Microvasculare pericytes are of key importance in neoformation of blood vessels, in stabilization of newly formed vessels as well as maintenance of angiostasis in resting tissues. In the present study the effects of the HDAC inhibitor VPA on pericyte proliferation, migration and differentiation was investigated. Furthermore, expression of genes known to be involved in different aspects of angiogenesis were investigated in primary pericyte cultures as well as the effects of VPA on the expression of these set of genes using quantative PCR arrays. The results show that HDAC inhibition leads to inhibition of pericyte proliferation and migration as well as pericyte differentiation into collagen type I producing fibroblasts. Furthermore, HDAC inhibition promoted expression of mRNAs of genes involved in vessel stabilization/maturation in human microvascular pericytes. The present study suggests that VPAs effect on angiogenesis via microvascular pericytes is through vessel stabilization.

Keyword [en]
pericyte HDACinhibitor VPA
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cell and Molecular Biology
Research subject
Biochemistry; Cell Research; Medical Biochemistry; Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-132608OAI: oai:DiVA.org:uu-132608DiVA: diva2:359879
Note

De två sista författarna delar förstaförfattarskapet

Available from: 2010-11-01 Created: 2010-10-22 Last updated: 2013-04-08
In thesis
1. The Role of Microvascular Pericytes in the Generation of Pro-fibrotic Connective Tissue Cells: Investigations in vitro and in Reactive Tissues in vivo
Open this publication in new window or tab >>The Role of Microvascular Pericytes in the Generation of Pro-fibrotic Connective Tissue Cells: Investigations in vitro and in Reactive Tissues in vivo
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pericytes are cells of mesenchymal origin located on the abluminal side, juxtapositioned to the endothelial cells in capillaries, venules and small arterioles. They are important for maintaining vessel integrity in resting tissues as well as the formation and stabilization of new vessels. They have been suggested to function as mesenchymal stem cells thereby contributing to the connective tissue cell population in reactive tissues. In this thesis the role of pericytes as progenitors for fibroblasts was further defined both in vitro and in vivo. In the first study connective tissue cells of mesenchymal origin were investigated based on their marker expression and relation to the microvasculature. The expression of alpha smooth muscle actin (α-SMA), a marker for myofibroblasts, was compared to the expression of certain integrins in three reactive conditions in human tissues. There was a co-localization of α-SMA and α1β1 integrins, indicating that α1 integrin was important for acquiring the α-SMA myofibroblast phenotype. To further investigate this, two animal models for carcinoma growth and wound healing using α1 deficient mice were employed. Reduction/lack of α-SMA expressing myofibroblasts substantiated or findings in human tissues, strengthening the hypothesis that the α1 integrin is important for the differentiation of α-SMA expressing myofibroblasts. In study two the effects of the HDAC inhibitor valproic acid (VPA) on pericyte function in vitro was investigated. This revealed that VPA had an inhibitory effect on pericyte proliferation, migration and differentiation into collagen type I producing fibroblasts. In addition qPCR array studies on angiogenesis related gene expression identified an up-regulation of genes involved in vessel stabilization in VPA treated pericytes. This suggests that VPA promotes a pericyte phenotype favoring vessel stability. In study three the differentiation from early mesenchymal stem cell like pericyte to fully differentiated fibroblast was further defined by flow cytometry marker analysis. By isolating pericytes from human placenta with a phenotype resembling the in vivo phenotype the differentiation pathway could be defined in five consecutive steps. The five steps were defined by their marker expression and their ability to give rise to the other cell populations in the differentiation lineage, as well as their slow cycling characteristics. A better understanding of how connective tissue cells are derived in fibrotic conditions may be beneficial in trying to modulate the outcome of the healing process towards optimal tissue regeneration with minimal fibrosis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 38 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 618
Keyword
pericyte fibroblast differentiation fibrosis
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Microbiology in the medical area Cell and Molecular Biology
Research subject
Medical Biochemistry; Cell Research; Microbiology
Identifiers
urn:nbn:se:uu:diva-132611 (URN)978-91-554-7938-1 (ISBN)
Public defence
2010-12-02, B42, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2010-11-11 Created: 2010-10-22 Last updated: 2011-01-13Bibliographically approved

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Christian, Sundberg

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