Differential Gene Expression in Human Cerebrovascular Malformations

Abstract

OBJECTIVE-We sought to identify genes with differential expression in cerebral cavernous malformations (CCMs), arteriovenous malformations (AVMs), and control superficial temporal arteries (STAs) and to confirm differential expression of genes previously implicated in the pathobiology of these lesions. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript METHODS-Total ribonucleic acid was isolated from four CCM, four AVM, and three STA surgical specimens and used to quantify lesion-specific messenger ribonucleic acid expression levels on human gene arrays. Data were analyzed with the use of two separate methodologies: gene discovery and confirmation analysis. RESULTS-The gene discovery method identified 42 genes that were significantly up-regulated and 36 genes that were significantly down-regulated in CCMs as compared with AVMs and STAs (P = 0.006). Similarly, 48 genes were significantly up-regulated and 59 genes were significantly down-regulated in AVMs as compared with CCMs and STAs (P = 0.006). The confirmation analysis showed significant differential expression (P < 0.05) in 11 of 15 genes (angiogenesis factors, receptors, and structural proteins) that previously had been reported to be expressed differentially in CCMs and AVMs in immunohistochemical analysis. CONCLUSION-We identify numerous genes that are differentially expressed in CCMs andAVMs and correlate expression with the immunohistochemistry of genes implicated in cerebrovascular malformations. In future efforts, we will aim to confirm candidate genes specifically related to the pathobiology of cerebrovascular malformations and determine their biological systems and mechanistic relevance. KeywordsArteriovenous malformations; Cavernous malformations; Gene arrays; Gene expression Cerebrovascular malformations (CVMs) are lesions with an abnormal vessel phenotype that predisposes patients to hemorrhagic strokes, seizures, focal neurological deficits, and other clinical manifestations (4,22). They include arteriovenous malformations (AVMs) and cerebral cavernous malformations (CCMs) and have distinct clinicopathological radiological profiles (14,30). The AVMs are tangled complexes of tortuous vessels representing fistulous connections between arteries and veins, and they lack an intervening capillary bed. They reveal preserved features of mature vessel wall phenotype altered by high flow and hemodynamic stress, including arterial, nidal, and venous aneurysms (5,6,28). The CCMs are characterized by caverns filled with blood or thrombus and are lined with a single layer of endothelial cells. These low-flow lesions are associated with brittle vasculature and repetitive oozing (5,6). The CCMs lack inter-endothelial cell tight junctions and mature vessel wall angio-architecture (8, 37).Little is known about the mechanisms of genesis or the progression of these lesions. Several proteins are abnormally expressed in AVMs and CCMs. Our group and others have demonstrated by performing immunohistochemical analysis that vascular endoth...

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