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Tytuł pozycji:

Adhesive and Proteolytic Phenotype of Migrating Endothelial Cells Induced by Thymosin β-4.

Tytuł:
Adhesive and Proteolytic Phenotype of Migrating Endothelial Cells Induced by Thymosin β-4.
Autorzy:
CIERNIEWSKI, CZESLAW S.
MALINOWSKI, MARIUSZ
BEDNAREK, RADOSLAW
CIERNIEWSKA‐CIESLAK, ALEKSANDRA
Temat:
THYMOSIN
PHENOTYPES
ENDOTHELIAL seeding
NEOVASCULARIZATION
FIBRIN tissue adhesive
SCAFFOLDING
VASCULAR endothelial growth factors
CELL migration
GENETIC mutation
Źródło:
Annals of the New York Academy of Sciences; Nov2007, Vol. 1112, p123-139, 17p, 4 Diagrams, 3 Graphs
Czasopismo naukowe
The early stages of angiogenesis are usually accompanied by the occurrence of vascular leakage, and the deposition of fibrin in extravascular spaces. Initially, the fibrin network acts as a sealing matrix, but later on also as a scaffolding for invading endothelial cells. This process is induced by angiogenic growth factors, particularly by vascular endothelial growth factor (VEGF). Angiogenesis involves proteolytic activities, in particular cell-bound urokinase/plasmin and matrix metalloproteinase (MMPs) activities that modulate the fibrin structure and affect adhesion and migration of endothelial cells. Recent data show that formation of new vessels may be stimulated by thymosin β-4 (Tβ-4), but it is still not clear whether Tβ-4 alone is angiogenic or the angiogenic potential of Tβ-4 is mediated by VEGF. In this report to further characterize Tβ-4 angiogenic activity, we produced its mutants that were deprived of the N-terminal tetrapeptide AcSDKP (Tβ-4(AcSDKPT/4A)), the actin-binding sequence KLKKTET (Tβ-4(KLKKTET/7A)) and with the nuclear localization sequence damaged by a point mutation Lys16Ala (Tβ-4(K16A)). Then we tested their activity to induce expression and release of MMPs as well as plasminogen activators inhibitor type-1 (PAI-1). We also analyzed their effect on migration and proliferation of endothelial cells in three-dimensional (3D) fibrin matrix as well as on their ability to stimulate the outgrowth of human endothelial cells in capillary-like tubular structures. Our data demonstrate that increased intracellular expression of Tβ-4 and its mutants is necessary and sufficient to induce PAI-1 gene expression in endothelial cells. Similarly, they stimulate expression and release of MMP-1, -2, and -3. As evaluated by using specific inhibitors to these MMPs, they modified specifically the structure of fibrin and thus facilitated migration of endothelial cells. To sum up, our data show that the mechanism by which Tβ-4 induced transition of endothelial cells from quiescent to proangiogenic phenotype is characterized by increased expression of PAI-1 and MMPs did not require the presence of the N-terminal sequence AcSDKP, and depended only partially on its ability to bind G-actin or to enter the nucleus. [ABSTRACT FROM AUTHOR]
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