Copyright © 2005, European Society of Cardiology
Pericytes influence endothelial cell growth characteristics: Role of plasminogen activator inhibitor type 1 (PAI-1)
aBiomedical Sciences Research Institute, University of Ulster, Coleraine, County Londonderry, BT52 1SA, Northern Ireland, United Kingdom
bSchool of Pharmacy, Queen's University Belfast, Belfast BT7 9BL, United Kingdom
* Corresponding author. School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT7 9BL, United Kingdom. Tel.: +44 28 9097 2360; fax: +44 28 9024 7794. Email address: T.Robson{at}qub.ac.uk
Objective: Pericytes, located in close proximity to the underlying endothelium, form an integral component of the microvasculature. These cells are intimately involved in angiogenesis, which is of fundamental importance in many physiological and pathological processes. We evaluated the influence of pericyte-conditioned medium (PCM) on endothelial cell growth characteristics and modulation of endothelial gene expression.
Methods: Migration and tubule formation assays were performed in vitro to determine the effect of PCM on endothelial growth characteristics. cDNA microarray analysis was used to identify alterations in gene expression following exposure of human microvascular endothelial cells (HMEC-1) to PCM. Overexpression of PAI-1 using recombinant protein or transient transfection, and inhibition using an inhibitory antibody against PAI-1, were used to determine whether up- or down-regulation of this gene was responsible for the changes in endothelial cell characteristics observed in response to PCM exposure.
Results: We have shown that PCM exerts a dramatic inhibitory influence on endothelial cell migration in vitro. In addition, endothelial cells cultured on MatrigelTM and exposed to PCM were found to generate significantly fewer angiogenic branches. Microarray analysis of endothelial cells exposed to PCM identified PAI-1 as the gene showing the greatest level of differential expression (3.4-fold induction). Studies using an inhibitory antibody to PAI-1 suggest that induction of this protein by PCM is pivotal to the observed inhibitory influence on the migratory and angiogenic potential of HMEC-1. We further investigated this by overexpressing PAI-1, which was shown to have a potent inhibitory influence on EC migration and angiogenic branching, although the concentration of PAI-1 was clearly important.
Conclusion: Collectively, these findings suggest that PCM contains a bioactive element(s) that controls both endothelial cell migration and tubule formation in vitro and that these responses may be partially controlled by increased endothelial cell expression of PAI-1.
KEYWORDS Pericytes; Endothelial cells; Angiogenesis; Microvasculature; Plasminogen activator inhibitor 1
1 Current address: Department of Surgery (SVUH), Faculty of Medicine, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland, United Kingdom.
2 Both authors contributed equally to the experimental data presented in the manuscript.
Time for primary review 11 days
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