Temporal patterns of gene expression after acute hindlimb ischemia in mice
insights into the genomic program for collateral vessel development
Cheol Whan Lee, MD*,
Eugenio Stabile, MD*,
Timothy Kinnaird, MD*,
Matie Shou, MD*,
Joseph M. Devaney, PhD* ,
Stephen E. Epstein, MD* and
Mary Susan Burnett, PhD*
* Laboratory of Vascular Biology, Cardiovascular Research Institute, MedStar Research Institute, Washington Hospital Center, Washington, DC, USA
Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA
Manuscript received April 14, 2003;
revised manuscript received September 12, 2003,
accepted September 15, 2003.
OBJECTIVES: We sought to understand the genomic program leading to collateral vessel formation.
BACKGROUND: Recently, technology has advanced to the point that it is now possible to elucidate the large array of genes that must be expressed, as well as the temporal expression pattern, for the development of functionally important collateral vessels. In this investigation, we used deoxyribonucleic acid array expression profiling to determine the time course of differential expression of 12,000 genes after femoral artery ligation in C57BL/6 mice.
METHODS: Ribonucleic acid was extracted from the adductor muscle, which showed no signs of ischemia. Sampling was at baseline, 6 h, and 1, 3, 7, and 14 days after femoral artery ligation or sham operation.
RESULTS: Femoral artery ligation caused the differential expression (>2-fold) of 783 genes at one or multiple time points: 518 were induced and 265 were repressed. Cluster analysis generated four temporal patterns: 1) early upregulated (6 to 24 h)—immediate early transcriptional factors, angiogenesis, inflammation, and stress-related genes; 2) mid-phase upregulated (day 3)—cell cycle and cytoskeletal and inflammatory genes; 3) late upregulated (days 7 to 14)—angiostatic, anti-inflammatory, and extracellular matrix-associated genes; and 4) downregulated—genes involved in energy metabolism, water channel, and muscle contraction. Microarray data were validated using quantitative reverse transcription polymerase chain reaction.
CONCLUSIONS: This study documents the large number of genes whose differential expression and temporal functional clustering appear to contribute to collateral formation. These results can serve as a genomic model for arteriogenesis and as a database for developing new therapeutic strategies.
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Abbreviations and Acronyms
| | cDNA | = complementary deoxyribonucleic acid | | ENA-78 | = epithelial neutrophil activating protein-78 | | HIF1 | = hypoxia-inducible factor-1 | | Hmox | = heme oxygenase | | HSP | = heat shock protein | | IL | = interleukin | | IP | = interferon-gamma-inducible protein | | MCP1 | = monocyte chemoattractant protein-1 | | MIG | = monokine induced by interferon-gamma | | MIP | = macrophage inflammatory protein | | MMP12 | = metalloelastase (metalloproteinase-12) | | MT1 | = metallothionein-1 | | RNA | = ribonucleic acid | | RT-PCR | = reverse transcription-polymerase chain reaction |
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