Tumor Angiogenesis Regulated by Gaseous Molecules in Tumor Microenvironment: Oxygen, pH, and Nitric Oxide

摘要

Hypoxia and acidosis are hallmarks of metabolic environment in solid tumors and regulate expression of vascular endothelial growth factor (VEGF), a key angiogenesis factor. We developed a novel in vivo microscopy technique to simultaneously measure VEGF promoter activity, pO_2 and pH. To monitor VEGF expression in vivo, we engineered human glioma cells that express green fluorescent protein (GFP) under the control of VEGF promoter. Tissue pO_2 and pH were determined by phosphorescence quenching microscopy and ratio imaging microscopy, respectively. These techniques have allowed us to show that VEGF transcription in brain tumors is regulated by tissue pO_2 and pH via distinct pathways. Nitric oxide (NO) is a multi functional gaseous molecule and regulates various physiological functions. We have shown that NO mediates vessel tone, blood flow, vascular permeability and leukocyte-endothelial interactions in solid tumors. Furthermore, we found that endothelial NO synthase (eNOS) plays predominant role in VEGF-induced angiogenesis and vascular permeability using angiogenic gel model in NOS deficient mice. These findings and the resulting mechanistic insights in the regulation of angiogenesis by gaseous molecules have significant implications for novel tumor detection and treatment strategies.