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Bcl2-induced vascular maturation

ABSTRACT: Overexpression of a caspase-resistant form of Bcl-2 (D34A) in human umbilical vein endothelial cells (EC) implanted into immunodeficient mice promotes the maturation of human EC-lined microvessels invested by vascular smooth muscle cells (VSMC) of mouse origin. In contrast, EC implants not overexpressing Bcl-2 form only simple, uncoated EC tubes. Here we compare the phenotypes of vessels formed in vivo and the transcriptomes in vitro of EC expressing different forms of Bcl-2. Wild type Bcl-2, like the caspase resistant D34A Bcl-2 mutant, is anti-apoptotic in vitro and promotes VSMC recruitment in vivo, whereas a G145E mutant that has diminished anti-apoptotic activity in vitro does not promote vessel maturation in vivo. The D34A and wild type forms of Bcl-2, but not the G145E mutant form of Bcl-2 significantly regulate RNA transcripts previously associated with EC-VSMC interactions and VSMC biology, including matrix Gla protein, insulin like growth factor binding protein (IGFBP)-2, matrix metaloproteinase-14 (MMP14), ADAM17 and Stanniocalcin-1. These effects of Bcl-2 on the transcriptome are detected in EC cultured as angiogenic 3-D tubes but are attenuated in EC cultured as 2-D monolayers. Bcl-2-regulated transcription in EC may contribute to vascular maturation, and support design of tissue engineering strategies using EC. Keywords: genetic modification, growth condition modification.

ORGANISM(S): Homo sapiens

PROVIDER: GSE10710 | GEO | 2008/03/05

SECONDARY ACCESSION(S): PRJNA107589

REPOSITORIES: GEO

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Project description:Radiotherapy has a critical role in the treatment of small cell lung cancer (SCLC). Effectiveness of radiation in SCLC remains limited as resistance results from defects in apoptosis. In the current study, we investigated whether using a Bcl-2/Bcl-XL inhibitor S44563 can enhance radiosensitivity of SCLC cells in vitro and in vivo. In vitro studies confirmed that S44563 induce apoptosis in SCLC cells by inducing hallmarks of apoptosis (cleaved caspase-3, sub-G1 fraction induction and induction of the mitochondrial caspase activation pathway). S44563 markedly enhanced sensitivity of H146 cells and H69 cells to radiation in clonogenic assay. In addition, the combination S44563 and cisplatin-based chemo-radiation showed a dramatic tumor growth delay and increased overall survival in mouse xenograft models. In vitro experiments demonstrated a greater induction of apoptosis (sub-G1 fraction and cleaved caspase-3) with the combination as well as in vivo caspase-3 immunostaining. This positive interaction between S44563 and radiation was greater when S44563 was given after the completion of the radiation, which may be explained by the radiation-induced over expression of anti-apoptotic proteins (Bcl-2 and Bcl-XL) through the NF-?B pathway activation. Taken together, these data underline the critical role of sequence administration of targeted therapies with conventional therapies. SCLC cells which survive to IR highly rely on the induction of anti apoptotic proteins in part through NF- ?B activation for their survival yielding to the concept of 'contextual oncogene addiction' to the Bcl-2/Bcl-XL pathway providing rational for targeting survival pathways to potentiate IR. For transcriptome analysis, 106 cells were seeded in T25 flasks, allowed to growth for 24 h, and then left untreated or treated with 2 Gy radiation. After 24 hours, cells were harvested, lysed for the extraction of RNA, and processed to analyze gene expression.The design of this study consists to 6 hybridizations in dual color with Agilent Human Genome 4x44K (design 014850). The reference is always the untreated condition.

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Bcl2-induced vascular maturation

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