VEGF Gene Expression in Adult Human Thymus Fat: A Correlative Study with Hypoxic Induced Factor and Cyclooxigenase-2

Francisco Tinahones,Rosa Bernal,Lourdes Garrido-Sanchez,Julian Salas,Fernando Cardona,Adrian Ruiz-Villalba,María Dolores Mayas,Manuel Macias-Gonzalez,Inmaculada Moreno-Santos,Rajaa El Bekay,Manuel Demora,Immo A Hansen

doi:10.1371/journal.pone.0008213

Abstract

It is well known that the adult human thymus degenerates into fat tissue; however, it has never been considered as a potential source of angiogenic factors. Recently, we have described that this fat (TAT) produces angiogenic factors and induces human endothelial cell proliferation and migration, indicating its potential angiogenic properties.DesignAdult thymus fat and subcutaneous adipose tissue specimens were obtained from 28 patients undergoing cardiac surgery, making this tissue readily available as a prime source of adipose tissue. We focused our investigation on determining VEGF gene expression and characterizing the different genes, mediators of inflammation and adipogenesis, and which are known to play a relevant role in angiogenesis regulation.ResultsWe found that VEGF-A was the isoform most expressed in TAT. This expression was accompanied by an upregulation of HIF-1α, COX-2 and HO-1 proteins, and by increased HIF-1 DNA binding activity, compared to SAT. Furthermore, we observed that TAT contains a high percentage of mature adipocytes, 0.25% of macrophage cells, 15% of endothelial cells and a very low percentage of thymocyte cells, suggesting the cellular variability of TAT, which could explain the differences in gene expression observed in TAT. Subsequently, we showed that the expression of genes known as adipogenic mediators, including PPARγ1/γ2, FABP-4 and adiponectin was similar in both TAT and SAT. Moreover the expression of these latter genes presented a significantly positive correlation with VEGF, suggesting the potential association between VEGF and the generation of adipose tissue in adult thymus.ConclusionHere we suggest that this fat has a potential angiogenic function related to ongoing adipogenesis, which substitutes immune functions within the adult thymus. The expression of VEGF seems to be associated with COX-2, HO-1 and adipogenesis related genes, suggesting the importance that this new fat has acquired in research in relation to adipogenesis and angiogenesis.

Highlights

It has been shown that the thymus grows rapidly during embryonic life and during childhood, reaching its maximum absolute size in puberty; thereafter growth ceases and involutes gradually until old age, when the gland is often smaller than at birth [1]
We observed that this fat (TAT) contains a high percentage of mature adipocytes, 0.25% of macrophage cells, 15% of endothelial cells and a very low percentage of thymocyte cells, suggesting the cellular variability of TAT, which could explain the differences in gene expression observed in TAT
Here we suggest that this fat has a potential angiogenic function related to ongoing adipogenesis, which substitutes immune functions within the adult thymus

Summary

Introduction

It has been shown that the thymus grows rapidly during embryonic life and during childhood, reaching its maximum absolute size in puberty; thereafter growth ceases and involutes gradually until old age, when the gland is often smaller than at birth [1] This age involution is shown by a decrease in the overall weight of the organ, associated lymphoid tissue atrophy and replacement by mature adipose tissue [1]. For this reason, all the studies carried out on adult thymus involution have been focused primarily on the immunological aspect, but has never been considered interesting enough to be studied as a potential source of humoral and angiogenic factors. VEGF has been used in numerous preclinical and early clinical gene or protein therapy trials with varying degrees of success [8]

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