RESUMEN
Fatty acid-binding proteins (FABP) are small molecular mass intracellular lipid chaperones that are expressed in a tissue-specific manner with some overlaps. FABP4 and FABP5 share ~55 % amino acid sequence homology and demonstrate synergistic effects in regulation of metabolic and inflammatory responses in adipocytes and macrophages. Recent studies have shown that FABP4 and FABP5 are also co-expressed in a subset of endothelial cells (EC). FABP4, which has a primarily microvascular distribution, enhances angiogenic responses of ECs, including proliferation, migration, and survival. However, the vascular expression of FABP5 has not been well characterized, and the role of FABP5 in regulation of angiogenic responses in ECs has not been studied to date. Herein we report that while FABP4 and FABP5 are co-expressed in microvascular ECs in several tissues, FABP5 expression is also detected in ECs of larger blood vessels. In contrast to FABP4, EC-FABP5 levels are not induced by VEGF-A or bFGF. FABP5 deficiency leads to a profound impairment in EC proliferation and chemotactic migration. These effects are recapitulated in an ex vivo assay of angiogenesis, the aortic ring assay. Interestingly, in contrast to FABP4-deficient ECs, FABP5-deficient ECs are significantly more resistant to apoptotic cell death. The effect of FABP5 on EC proliferation and survival is mediated, only in part, by PPARδ-dependent pathways. Collectively, these findings demonstrate that EC-FABP5, similar to EC-FABP4, promotes angiogenic responses under certain conditions, but it can also exert opposing effects on EC survival as compared to EC-FABP4. Thus, the balance between FABP4 and FABP5 in ECs may be important in regulation of angiogenic versus quiescent phenotypes in blood vessels.
Asunto(s)
Linaje de la Célula , Proteínas de Unión a Ácidos Grasos/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Metabolismo de los Lípidos , Proteínas de Neoplasias/metabolismo , Neovascularización Fisiológica , Animales , Aorta/fisiología , Muerte Celular , Proliferación Celular , Supervivencia Celular , Quimiotaxis , Citoprotección , Proteínas de Unión a Ácidos Grasos/deficiencia , Células Endoteliales de la Vena Umbilical Humana/citología , Técnicas In Vitro , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Neoplasias/deficiencia , PPAR delta/metabolismoRESUMEN
The role of cytosolic calcium oscillation has long been recognized in the regulation of cellular and molecular interactions. Information embedded in calcium oscillation can provide molecular cues for cell behavior such as cell differentiation. Although calcium dynamics are versatile and likely to depend on the cell type, the calcium dynamics in human mesenchymal stem cells (hMSCs) and its role in differentiation are yet to be fully elucidated. In the present study we characterized the calcium oscillation profiles in hMSCs before and after subjecting the cells to the osteoinductive factors. Our findings indicate that the calcium spikes decreased rapidly with osteodifferentiation to a level observed in terminally differentiated human osteoblasts. In addition, the calcium oscillations appear to serve as a bidirectional signal during hMSC differentiation. While an altered calcium oscillation pattern may be an indicator for hMSC differentiation, it is also likely to be involved in directing hMSC differentiation. Treatment of hMSCs with a noninvasive electrical stimulation, for example, not only altered the calcium oscillations but also facilitated osteodifferentiation. Regulation of calcium oscillation by external physical stimulation could amplify hMSC differentiation into a tissue-specific lineage and may offer an alternate biotechnology to harness the unique properties of stem cells.