Differential Gene Expression in Human Cerebrovascular Malformations

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 endothelial growth factor (VEGF) and the VEGF receptors VEGF-r1 (flt1) and VEGF-r2 (flk1) are overexpressed in both AVMs and CCMs compared with normal brain vessels (21, 35). Fibronectin is expressed to a greater extent in CCMs than in AVMs, consistent with the proliferative immature vessel phenotype (21). Laminin and smoothelin, both of which reflect mature vessel wall phenotype, are underexpressed in CCMs as compared with AVMs (21, 34). Distinct genes have been identified that predispose individuals to familial manifestations of these lesions, which is related to transforming growth factor-β receptor binding proteins (1, 13, 18, 19) and the Krev Interaction Trapped 1 (krit1) signaling pathway (9, 17, 23, 26, 32) for AVMs and CCMs, respectively. We hypothesize that different groups of genes are involved in the pathogenesis of AVMs and CCMs and that other genes are nonspecifically associated with both lesion types. In the experiments described in this article, we applied gene microarray analysis to correlate alterations in ribonucleic acid (RNA) transcription in AVMs and CCMs to the previously published abnormal protein expression in these lesions. In addition, we found numerous other genes differentially expressed in one or both lesion types, which has not been reported previously.