Effects of the Histone Deacetylase Inhibitor Valproic Acid on Human Pericytes In Vitro

Jakob Karén,Lennart Dencker,Tomas Friman,Birger Scholz,Alejandro Rodriguez,Christian Sundberg,Jeffrey M Gimble

doi:10.1371/journal.pone.0024954

Jakob Karén, Lennart Dencker + Show 5 more

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https://doi.org/10.1371/journal.pone.0024954

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Journal: PloS one	Publication Date: Sep 22, 2011
Citations: 76	License type: CC BY 4.0

Affiliation: Uppsala University, Uppsala University Hospital

Abstract

Microvascular 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. Furthermore, pericytes are capable of differentiating into pro-fibrotic collagen type I producing fibroblasts. The present study investigates the effects of the histone deacetylase (HDAC) inhibitor valproic acid (VPA) on pericyte proliferation, cell viability, migration and differentiation. The results show that HDAC inhibition through exposure of pericytes to VPA in vitro causes the inhibition of pericyte proliferation and migration with no effect on cell viability. Pericyte exposure to the potent HDAC inhibitor Trichostatin A caused similar effects on pericyte proliferation, migration and cell viability. HDAC inhibition also inhibited pericyte differentiation into collagen type I producing fibroblasts. Given the importance of pericytes in blood vessel biology a qPCR array focusing on the expression of mRNAs coding for proteins that regulate angiogenesis was performed. The results showed that HDAC inhibition promoted transcription of genes involved in vessel stabilization/maturation in human microvascular pericytes. The present in vitro study demonstrates that VPA influences several aspects of microvascular pericyte biology and suggests an alternative mechanism by which HDAC inhibition affects blood vessels. The results raise the possibility that HDAC inhibition inhibits angiogenesis partly through promoting a pericyte phenotype associated with stabilization/maturation of blood vessels.

Highlights

Microvascular pericytes are cells of mesenchymal origin situated juxtaposition to the endothelial layer in the microvasculature i.e. capillaries, venules and small arterioles
We have developed methods to isolate and propagate pericytes from placenta and neonatal skin which has enabled the study of pericyte biology and in particular their differentiation into collagen type I producing fibroblasts, a process that spontaneously takes place when pericytes are cultured in the presence of 10% fetal calf serum (FCS) [6,7,8,9]
To determine if valproic acid (VPA) had histone deacetylase (HDAC) inhibitory effects in pericytes, we assessed the levels of acetylated histone H4 in pericytes exposed to 1 mM VPA and non-treated control (NTC) pericytes

Summary

Introduction

Microvascular pericytes are cells of mesenchymal origin situated juxtaposition to the endothelial layer in the microvasculature i.e. capillaries, venules and small arterioles. They are continuous with the vascular basement membrane. Pericytes have a central role in the structural and functional integrity of the microvascular bed in resting tissues Their equivalents in larger vessels are smooth muscle cells [1]. In addition to endothelial cells, must be tightly controlled in order to maintain tissue homeostasis, optimize tissue repair and regeneration. Their role in tissue repair is further highlighted by their ability to act as multipotent mesenchymal stem cells. Pericytes have been shown to differentiate into smooth muscle cells and myofibroblasts, and in vitro to osteoblasts, adipocytes and chondroblast [4,5]

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