Thrombospondin-1, PECAM-1, and regulation of angiogenesis


  • Nader Sheibani
  • W. A. Frazier


CD31, endothelial cells, thrombospondins


Thrombospondin-l (TSPl) is a multidomain glycoprotein expressed by many cell types. It is a multifunctional protein with important roles in regulation of vascular cell functions. Mutation or loss of tumor suppressor genes results in down regulation of TSPl expression during malignant transformation. Thus, suggesting that down regulation of TSPl may contribute to development of the tumor angiogenic phenotype and perhaps tumor metastasis. TSPl was demonstrated to be a natural inhibitor of angiogenesis. Peptides from procollagen-like domain and type 1 repeats of TSP1, like whole TSP1, inhibit the angiogenic response to a variety of angiogenic stimuli in vivo and endothelial cell (EC) migration in vitro by directly acting on ECs. The molecular mechanisms which mediate these inhibitory effects of TSPl and its peptides are not understood. TSPl expression is down regulated in the Polyoma middle T transformed mouse brain ECs (bEND.3). This may remove the TSPl inhibitory effects allowing ECs to rapidly proliferate in culture and form hemangiomas in vivo. Re-expression of TSPl in bEND.3 cells restores a normal phenotype and suppresses their ability to form hemangiomas. This is mediated by modulating expression of several genes in concert favoring a differentiated state of endothelium. TSPl transfected bEND.3 cells down regulate expression of PECAM-1, a multifunctional endothelial cell adhesion molecule with essential roles in angiogenesis. A similar phenotype to that of TSPl transfected cells was observed when endogenous PECAM-1 levels were down regulated by anti-sense transfection of bEND.3 cells. The anti-sense PECAM-1 transfected cells turn on expression of endogenous TSPl and its angioinhibitory receptor, CD36. Expression of other genes with potential roles in regulation of EC phenotype were also affected in patterns very similar to those observed in TSPl transfected bEND.3 cells. Therefore, it appears that a reciprocal relationship exists between TSPl and PECAM-1 such that they are constituents of a "switch" that regulates in concert many components of the angiogenic and differentiated phenotype of ECs.




Invited Reviews