Antiapoptotic activities of bcl-2 correlate with vascular maturation and transcriptional modulation of human endothelial cells

Endothelium. 2008 Jan-Feb;15(1):59-71. doi: 10.1080/10623320802092393.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Blood Vessels / cytology
  • Blood Vessels / physiology
  • Cell Culture Techniques
  • Cells, Cultured
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism*
  • Endothelial Cells / transplantation
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism*
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, SCID
  • Models, Genetic
  • Muscle, Smooth, Vascular / metabolism
  • Mutation
  • Organ Culture Techniques
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Retroviridae / genetics
  • Transcription, Genetic*
  • Transduction, Genetic
  • Transfection
  • Transplantation, Heterologous
  • Umbilical Veins / cytology

Substances

  • Proto-Oncogene Proteins c-bcl-2