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CLINICAL RESEARCH: ATHEROSCLEROSIS

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

Judith C. Sluimer, MSc^_*, Jean-Marie Gasc, PhD, Job L. van Wanroij, MD, Natasja Kisters, BSc^_*, Mathijs Groeneweg, MSc^_*, Maarten D. Sollewijn Gelpke, MSc^||, Jack P. Cleutjens, PhD^_*, Luc H. van den Akker, MD^¶, Pierre Corvol, MD, PhD, Bradly G. Wouters, PhD, Mat J. Daemen, MD, PhD^_*,_* and Ann-Pascale J. Bijnens, PhD^_*

^_* Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, Maastricht, the Netherlands
Department of Surgery, University of Maastricht, Maastricht, the Netherlands
Maastricht Radiation Oncology Lab (Maastro), Research Institute Growth and Development (GROW), University of Maastricht, Maastricht, the Netherlands
Collège-de-France, INSERM U36, Paris, France
^|| Department of Molecular Design and Informatics, NV Organon, Oss, the Netherlands
^¶ Department of Surgery, Maasland Hospital, Sittard, the Netherlands.

Manuscript received July 31, 2007; revised manuscript received November 20, 2007, accepted December 10, 2007.

^_* Reprint requests and correspondence: Dr. Mat Daemen, Department of Pathology, University of Maastricht, P.O. Box 5800, 6202 AZ Maastricht, the Netherlands. (Email: Mat.Daemen{at}path.unimaas.nl).

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 HIF1, HIF2, 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

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