Endothelial cell apoptotic genes associated with the pathogenesis of thrombotic microangiopathies: An application of oligonucleotide genechip technology

Idiopathic thrombotic thrombocytopenic purpura (TTP) is a disease character ized by the apoptotic injury of all microvascular endothelial cells (MVEC) except those of pulmonary origin. It notably also spares EC of large vessel origin. It is fatal unless treated with plasma exchange. The EC lineage re striction of the apoptotic lesions in vivo is reproduced in vitro following exposure of primary human MVEC derived from various tissues to TTP plasma. Oligonucleotide genechip technology was used to identify genes that may co ntribute to the resistance of lung MVEC to apoptosis induced by TTP plasma and to explore the intrinsic genotypic heterogeneity between MVEC of TTP-se nsitive (skin) versus resistant (lung) lineage. Exposure of cells to TTP or normal plasma yielded 157 genes that were differentially expressed in prim ary human lung MVEC. A global change in expression of pro- and anti-apoptot ic genes was seen, including increases in caspase 1, Fas, and Bcl-xl, alrea dy shown by experimental means to be involved in TTP pathogenesis. Addition al differences suggest the importance of pathways related to the death rece ptor ligand TRAIL, as well as a role for disruption of EC-extracellular mat rix interactions in the initiation of apoptosis. Maintenance of specific pr osurvival signals at baseline may be a feature of lung MVEC resistance in T TP as suggested by higher expression than skin EC of 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). (C) 2001 Aca demic Press.