Publication: Thrombospondin-1, PECAM-1, and regulation of angiogenesis
Authors
Sheibani, N. ; Frazier, W.A.
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
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.
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