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NF-kappaB mediates alphavbeta3 integrin-induced endothelial cell survival
M Scatena1, M Almeida, M L Chaisson
1Department of Pathology, University of Washington, Seattle, Washington 98195, USA. mscatena@u.washington.edu
The Journal of Cell Biology
|June 20, 1998
Summary
The alphavbeta3 integrin promotes endothelial cell survival by activating nuclear factor-kappa B (NF-kappaB). This pathway is crucial for angiogenesis and is regulated by specific extracellular matrix molecules like osteopontin.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Endothelial cell apoptosis is a key regulator of angiogenesis.
- The alphavbeta3 integrin is implicated in inhibiting endothelial cell apoptosis.
- The precise molecular mechanisms underlying alphavbeta3 integrin-mediated cell survival remain largely unknown.
Purpose of the Study:
- To elucidate the role of nuclear factor-kappa B (NF-kappaB) in alphavbeta3 integrin-mediated endothelial cell survival.
- To investigate the signaling pathways involved in NF-kappaB activation by alphavbeta3 integrin ligands.
- To determine the contribution of NF-kappaB to the anti-apoptotic effects of specific extracellular matrix proteins.
Main Methods:
- Cultured rat aorta-derived endothelial cells.
- Treatment with various extracellular matrix molecules (osteopontin, collagen type I, fibronectin, laminin, vitronectin).
- Assessment of endothelial cell apoptosis via serum withdrawal.
- Measurement of NF-kappaB activity using gel shift assays and reporter gene assays.
- Inhibition of NF-kappaB using nonphosphorylatable IkappaB.
- Utilized dominant-negative mutants for Ras and Src, and inhibitors for MEK and PI3-kinase.
Main Results:
- Osteopontin and beta3 integrin ligation significantly increased NF-kappaB activity, involving p65 and p50 subunits.
- alphavbeta3 integrin was essential for osteopontin-induced NF-kappaB activation and cell survival; blocking it induced apoptosis.
- NF-kappaB activation was indispensable for survival induced by osteopontin and vitronectin but not by fibronectin, laminin, or collagen type I.
- Osteopontin-mediated NF-kappaB activation was dependent on Ras and Src signaling pathways.
- MEK and PI3-kinase inhibition did not affect NF-kappaB activation by osteopontin.
Conclusions:
- Nuclear factor-kappa B (NF-kappaB) is identified as a critical signaling molecule in alphavbeta3 integrin-mediated endothelial cell survival.
- The study highlights a specific mechanism by which alphavbeta3 integrin signaling promotes angiogenesis through NF-kappaB activation.
- These findings provide insights into the molecular regulation of endothelial cell fate during angiogenesis.