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.
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
David R
DR
Enis
Benjamin
B
Dunmore
Nicola
N
Johnson
Jordan S
JS
Pober
Cristin G
CG
Print
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