Angiogenesis

, Volume 10, Issue 1, pp 55–68 | Cite as

Vascular development is disrupted by endothelial cell-specific expression of the anti-apoptotic protein Bcl-2

  • Hélène Duval
  • Nicola Johnson
  • Jia Li
  • Amanda Evans
  • Shuo Chen
  • Diana Licence
  • Jeremy Skepper
  • D. Stephen Charnock-Jones
  • Stephen Smith
  • Cristin Print
Original Paper
First Online:
Received:
Accepted:

Abstract

Endothelial cell (EC) apoptosis has been detected in remodelling blood vessels in vivo, and inhibition of EC apoptosis appears to alter vascular morphogenesis in vitro, suggesting that EC apoptosis may play a role in blood vessel remodelling. However, apoptotic EC are difficult to quantify in vivo, and studies of the incidence of EC apoptosis and the sites at which it occurs in vivo have produced contradictory results. Therefore, the specific biological roles played by EC apoptosis remain unclear. Here, we have used a transgenic approach to determine the biological function of EC apoptosis in vivo. Anti-apoptotic Bcl-2 transgenes were expressed in mice under control of the EC-specific tie2 promoter. These transgenic mice died during the second half of gestation. While the development and remodelling of large vessels including aortic arch arteries and great veins proceeded normally, abnormally dense and disorganised networks of small vessels were present in the skin and internal organs. In addition, vessel organisation and lumen formation were disrupted in the placental labyrinth. This study provides direct experimental evidence that endothelial cell apoptosis plays an essential role during embryogenesis. Our results suggest that EC apoptosis plays an important role in determining the structure of the microcirculation but may be dispensable for large vessel development.

Keywords

Apoptosis Endothelial Angiogenesis Vascular regression Bcl-2 Transgenic 

Abbreviations

EC

Endothelial cell

HUVEC

Human umbilical vein EC

BAEC

Bovine aortic EC

TNF

Tumour necrosis factor

FCS

Foetal calf serum

PCR

Polymerase chain reaction

eGFP

Enhanced green fluorescent protein

IRES

Internal ribosome entry site

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Notes

Acknowledgements

We wish to acknowledge the Transgenic Unit of Cambridge University Central Biomedical Services for assistance with the generation of transgenic mice. Dr Cecile Goujet (SEAT, Villejuif, France) provided training and assistance with transgenic mouse generation. Professor Thomas Sato (University of Texas Southwestern Medical Centre, USA) provided mouse tie2 gene sequences. Dr Sarah Ogilvy (Cambridge University Department of Haematology) provided human Bcl-2 sequences. Dr Graham Burton and Professor Anne Ferguson-Smith (Department of Anatomy, Cambridge University) and Professor Jordan Pober (Yale University) provided advice on phenotype interpretation. Daniel Hurley and Anita Muthukaruppan provided advise on the manuscript. This project was funded by a Medical Research Council UK component grant. Jai Li and Shou Chen were supported by a St. Edmund’s College Cambridge Scholarship donated by Dr Ming-Wei Wang of China.

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Copyright information

© Springer Science + Business Media B.V. 2006

Authors and Affiliations

  • Hélène Duval
    • 1
  • Nicola Johnson
    • 1
  • Jia Li
    • 1
  • Amanda Evans
    • 1
  • Shuo Chen
    • 1
  • Diana Licence
    • 1
  • Jeremy Skepper
    • 2
  • D. Stephen Charnock-Jones
    • 3
  • Stephen Smith
    • 3
  • Cristin Print
    • 1
    • 4
  1. 1.Department of PathologyCambridge UniversityCambridgeUK
  2. 2.Multi-imaging Centre, Department of AnatomyCambridge UniversityCambridgeUK
  3. 3.Department of Obstetrics and GynaecologyCambridge University, Rosie HospitalCambridgeUK
  4. 4.Department of Molecular Medicine and PathologySchool of Medical Sciences, University of AucklandAucklandNew Zealand

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