M-CSF Signals through the MAPK/ERK Pathway via Sp1 to Induce VEGF Production and Induces Angiogenesis In Vivo

BACKGROUND: M-CSF recruits mononuclear phagocytes which regulate processes such as angiogenesis and metastases in tumors. VEGF is a potent activator of angiogenesis as it promotes endothelial cell proliferation and new blood vessel formation. Previously, we reported that in vitro M-CSF induces the expression of biologically-active VEGF from human monocytes. METHODOLOGY AND RESULTS: In this study, we demonstrate the molecular mechanism of M-CSF-induced VEGF production. Using a construct containing the VEGF promoter linked to a luciferase reporter, we found that a mutation reducing HIF binding to the VEGF promoter had no significant effect on luciferase production induced by M-CSF stimulation. Further analysis revealed that M-CSF induced VEGF through the MAPK/ERK signaling pathway via the transcription factor, Sp1. Thus, inhibition of either ERK or Sp1 suppressed M-CSF-induced VEGF at the mRNA and protein level. M-CSF also induced the nuclear localization of Sp1, which was blocked by ERK inhibition. Finally, mutating the Sp1 binding sites within the VEGF promoter or inhibiting ERK decreased VEGF promoter activity in M-CSF-treated human monocytes. To evaluate the biological significance of M-CSF induced VEGF production, we used an in vivo angiogenesis model to illustrate the ability of M-CSF to recruit mononuclear phagocytes, increase VEGF levels, and enhance angiogenesis. Importantly, the addition of a neutralizing VEGF antibody abolished M-CSF-induced blood vessel formation. CONCLUSION: These data delineate an ERK- and Sp1-dependent mechanism of M-CSF induced VEGF production and demonstrate for the first time the ability of M-CSF to induce angiogenesis via VEGF in vivo

Relatório de estágio em farmácia comunitária

Relatório de estágio realizado no âmbito do Mestrado Integrado em Ciências Farmacêuticas, apresentado à Faculdade de Farmácia da Universidade de Coimbr

Graphite Ablation Experiments in the LHMEL Laser Facility

Understanding the surface reactions of ablating materials is an important need for modeling Thermal Protection Systems (TPS). There are many experiments out there that capture ablation phenomena seen in hypersonic flows, but ones that can be used to validate Computational Fluid Dynamics (CFD) codes are limited. Most experiments are conducted in arcjet wind tunnels where the enthalpy of the flow is increased by plasma heating due to arc discharges. These flows are hard to characterize due to the unknown dissociated state of the flow that varies spatially along the length of the plasma jet exiting the arc heater. These types of experiments are best for engineering design and not for looking at fundamental physics of surface chemistry. Other options for experimentally measuring surface reaction rates are in ovens or by laser heating of the surface. Laser ablation testing is currently conducted by the Air Force Research Lab Materials Directorate in the LHMEL facility. This work will describe an effort to conduct experiments to be used as validation tools for modeling surface reaction rates

Effect of Modeling Hypersonic Flow Physics on Electro-Optical Sensor Assessment

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143108/1/6.2017-3836.pd