The Use of Arrays to Study the Vasculature

Microarray technology has been successfully used in several studies regarding the vasculature, including the identification of cell-type enriched transcripts, the basis of pathological disease, and the external response to stimuli in a cell type-specific fashion.

For example, microarray technology has been successfully used to investigate the mechanism of cell-type resistance to apoptotic effects of the fatal disease idiopathic thrombotic thrombocytopenic purpura (TTP) [1]. TTP is a disease characterized by the apoptotic injury of all microvascular endothelial cells (MVECs) except those of pulmonary origin. Oligonucleotide gene chip technology identified genes differentially overexpressed in TTp-resistant (lung) MVECs relative to TTP-sensitive (skin) MVECs and hence that may contribute to the resistance of lung MVECs to be resistant to apoptosis induced by TTP plasma. This study showed that exposure of cells to TTP plasma yielded 157 genes that were overexpressed in primary human lung MVEC, including specific pro-survival signals such as the TRAIL antagonist, osteoprotegerin, and the vascular endothelial growth factors, VEGF/VPF and VEGF-C, and their receptors, VEGFR-2 (KDR) and VEGFR-3 (Flt4) [1].

Similar studies identified genes overexpressed in angio-genesis. Angiogenesis is a key process in a variety of human diseases, including cancer. The ability to target selectively the tumor vasculature is potentially useful for the diagnosis and treatment of cancer. Tumor endothelial cells (TECs), in contrast to normal endothelial cells, are resistant to apopto-sis, are proadhesive for renal carcinoma cells, and are able to grow and organize in the absence of serum in persistent capillary-like structures [2]. cDNA array technology was recently used to identify markers specific for TECs [2, 3]. In one study, IGFBP-3 was found to be restricted exclusively to ECs, indicating that IGFBP-3 is a potential novel marker of angiogenesis. In another study, expression of angiopoi-etin-1 and vascular endothelial growth factor (VEGF)-D and the Akt survival pathway were markedly upregulated in TECs. These results suggest the possibility of using IGFBP-3, VEGF-D, or the Akt pathway as therapeutic targets for antiangiogenic strategies.

DNA array technology has been recently used to establish a molecular link between hyperhomocystinemia (HHCy) and atherosclerosis. Microarray analysis showed that homocysteine (Hcy) was linked to cholesterol dysregu-

lation by showing that Hcy treatment of human umbilical vein endothelial cells (HUVECs) resulted in the upregula-tion of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), an enzyme involved with cholesterol synthesis [4]. Further biochemical analysis performed in this study confirmed that Hcy resulted in an increase in cellular cholesterol levels, suggesting a novel solid explanation for the observed proatherogenic effect of Hcy.

In addition, gene array systems were used to study the cellular response of endothelial cells to external stimuli. In one study, the response of human dermal microvascular endothelial cell (DMVEC) cultures to infection by Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) was analyzed [5]. Significant dysregulation was shown of several cytokine-related genes or receptors, as well as endothelial cell and macrophage markers and other genes associated with angiogenesis or transformation. Microarrays have also been used to analyze changes in gene expression following stimulation of myometrial microvascular endothelial cells (MMECs) with vascular endothelial growth factor (VEGF). In this study, a total of 110 genes were identified as upregu-lated by VEGF, the vast majority of which (81%) were not previously reported as upregulated by VEGF or by angiogenesis [6].

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