| Autor: |
Bayless, K. J., Kang, H., Duran, C. L., Abbey, C. A., Kwak, H., Dave, J. M., Kaunas, R. R., Maxwell, S. A. |
| Předmět: |
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| Zdroj: |
Proceedings of the Physiological Society; 2013, p100P-101P, 2p |
| Abstrakt: |
Endothelial cells normally line the vasculature and remain quiescent. However, these cells can be rapidly stimulated to initiate new blood vessel formation given the proper cues. This study reports a new mechanism for initiating angiogenic sprout formation that involves vimentin, the major intermediate filament protein in endothelial cells. We utilized two models to stimulate endothelial sprouting responses into three-dimensional collagen matrices, where sphingosine 1-phosphate (S1P) was combined with either growth factors (GF) or wall shear stress (WSS). Initial studies confirmed vimentin was required for both S1P + GF- and S1P + WSS-induced endothelial cell invasion. We also observed that vimentin was cleaved by calpains during invasion. Calpains were predominantly activated by GF and were required for sprout initiation. Because others have reported membrane type 1 - matrix metalloproteinase (MT1- MMP) is required for endothelial sprouting responses, we tested whether vimentin and calpain acted upstream of MT1- MMP. Both calpain and vimentin were required for successful MT1-MMP membrane translocation in both invasion systems, which shared a common activation by S1P. In addition, vimentin complexed with MT1-MMP in a manner that required both the cytoplasmic domain of MT1-MMP and calpain activation, which increased the soluble pool of vimentin in endothelial cells. Altogether, these in vitro data indicate that pro-angiogenic signals converge to activate calpain-dependent vimentin cleavage and increase vimentin solubility, which act upstream to facilitate MT1-MMP membrane translocation, resulting in successful endothelial sprout formation in three-dimensional collagen matrices. To confirm these data in an in vivo model, wound healing studies were conducted in mice anesthetized with a ketamine/xylazine cocktail in an acceptable plane of anesthesia. Mice were treated with FTY720, a pharmacological antagonist of S1P or vehicle control. Compared to vehicle, FTY720 treatment significantly reduced vascular density at 9 days of wound healing. In addition, mice lacking vimentin exhibited reduced angiogenic responses compared to wild-type littermates. These data help reinforce a requirement for S1P in angiogenic responses in vivo, as well as a critical role for vimentin in angiogenic responses during wound healing. In addition, these findings help explain why S1P synergizes with GF and WSS to stimulate robust sprouting in 3D collagen matrices. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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