Clinical Research
Atherosclerosis
Hypoxia, Hypoxia-Inducible Transcription Factor, and Macrophages in Human Atherosclerotic Plaques Are Correlated With Intraplaque Angiogenesis

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Objectives

We sought to examine the presence of hypoxia in human carotid atherosclerosis and its association with hypoxia-inducible transcription factor (HIF) and intraplaque angiogenesis.

Background

Atherosclerotic plaques develop intraplaque angiogenesis, which is a typical feature of hypoxic tissue and expression of HIF.

Methods

To examine the presence of hypoxia in atherosclerotic plaques, the hypoxia marker pimonidazole was infused before carotid endarterectomy in 7 symptomatic patients. Also, the messenger ribonucleic acid (mRNA) and protein expression of HIF1α, HIF2α, HIF-responsive genes (vascular endothelial growth factor [VEGF], glucose transporter [GLUT]1, GLUT3, hexokinase [HK]1, and HK2), and microvessel density were determined in a larger series of nondiseased and atherosclerotic carotid arteries with microarray, quantitative reverse transcription polymerase chain reaction, in situ hybridization, and immunohistochemistry.

Results

Pimonidazole immunohistochemistry demonstrated the presence of hypoxia, especially within the macrophage-rich center of the lesions. Hypoxia correlated with the presence of a thrombus, angiogenesis, and expression of CD68, HIF, and VEGF. The mRNA and protein expression of HIF, its target genes, and microvessel density increased from early to stable lesions, but no changes were observed between stable and ruptured lesions.

Conclusion

This is the first study directly demonstrating hypoxia in advanced human atherosclerosis and its correlation with the presence of macrophages and the expression of HIF and VEGF. Also, the HIF pathway was associated with lesion progression and angiogenesis, suggesting its involvement in the response to hypoxia and the regulation of human intraplaque angiogenesis.

Abbreviations and Acronyms

EC
endothelial cell
GLUT
glucose transporter
HIF
hypoxia-inducible transcription factor
HK
hexokinase
KiEC
proliferating, Ki-67+ endothelial cell
qRT-PCR
quantitative reverse transcription-polymerase chain reaction
ROS
reactive oxygen species
VEGF
vascular endothelial growth factor

Cited by (0)

The authors participate in the European Vascular Genomics Network, a Network of Excellence supported by the European Community’s Sixth Framework Program for Research Priority 1 (contract LSHM-CT-2003-503254). Research was supported in part by grants from the van Walree Fund, Royal Netherlands Academy of Arts and Sciences, the Innovational Research Veni program of the Netherlands Organization of Scientific Research (grant 916.046.083), and the SenterNovem agency of the Dutch Ministry of Economic Affairs (grant TSGE3088).