Antiapoptotic activities of bcl-2 correlate with vascular maturation and transcriptional modulation of human endothelial cells.
Overexpression of a caspase-resistant form of Bcl-2 (D34A) in human umbilical vein endothelial cells (ECs) implanted into immunodeficient mice promotes the maturation of human EC-lined microvessels invested by vascular smooth muscle cells (VSMCs) of mouse origin. In contrast, EC implants not overexpressing Bcl-2 form only simple, uncoated EC tubes. Here the authors 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 antiapoptotic in vitro and promotes VSMC recruitment in vivo, whereas a G145E mutant that has diminished antiapoptotic 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 metalloproteinase (MMP)-14, ADAM17, stanniocalcin-1, and targets of the nuclear factor (NF)-kappa B, cAMP response element-binding (CREB), and activator protein 1 (AP1) transcription factor families. These effects of Bcl-2 on the transcriptome are detected in ECs cultured as angiogenic three-dimensional (3-D) tubes but are attenuated in ECs cultured as 2-D monolayers. Bcl-2-regulated transcription in ECs may contribute to vascular maturation, and support design of tissue engineering strategies using EC.
Enis
David R
DR
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
Dunmore
Benjamin
B
Johnson
Nicola
N
Pober
Jordan S
JS
Print
Cristin G
CG
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001808:Blood Vessels / Q000166:cytology / Q000502:physiology; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D008957:Models, Genetic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009154:Mutation; D009924:Organ Culture Techniques; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D014158:Transcription, Genetic; D014161:Transduction, Genetic; D014162:Transfection; D014183:Transplantation, Heterologous; D014471:Umbilical Veins / Q000166:cytology
D019253:Proto-Oncogene Proteins c-bcl-2