Vascular endothelial growth factor (VEGF) is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions. VEGF has also been implicated in pathological angiogenesis associated with tumors, intraocular neovascular disorders and other conditions. The biological effects of VEGF are mediated by two receptor tyrosine kinases (RTKs), VEGFR-1 and VEGFR-2, which differ considerably in signaling properties. Non-signaling co-receptors also modulate VEGF RTK signaling. Currently, several VEGF inhibitors are undergoing clinical testing in several malignancies. VEGF inhibition is also being tested as a strategy for the prevention of angiogenesis, vascular leakage and visual loss in age-related macular degeneration.

The biology of VEGF and its receptors.

Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main molecular mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.

http://www.chem.uwec.edu/Chem454/BiochemDiabetes.pdf

Biochemistry and molecular cell biology of diabetic complications

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in a variety of in vivo models. Hypoxia has been shown to be a major inducer of VEGF gene transcription. The tyrosine kinases Flt-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2) are high-affinity VEGF receptors. The role of VEGF in developmental angiogenesis is emphasized by the finding that loss of a single VEGF allele results in defective vascularization and early embryonic lethality. VEGF is critical also for reproductive and bone angiogenesis. Substantial evidence also implicates VEGF as a mediator of pathological angiogenesis. In situ hybridization studies demonstrate expression of VEGF mRNA in the majority of human tumors. Anti-VEGF monoclonal antibodies and other VEGF inhibitors block the growth of several tumor cell lines in nude mice. Clinical trials with various VEGF inhibitors in a variety of malignancies are ongoing. Very recently, an anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the Food and Drug Administration as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy. Furthermore, VEGF is implicated in intraocular neovascularization associated with diabetic retinopathy and age-related macular degeneration.

/pdf/vascular-endothelial-growth-factor-basic-science-and-17gyy6h97s.pdf

Vascular endothelial growth factor: basic science and clinical progress.

Vascular endothelial growth-factor receptors (VEGFRs) regulate the cardiovascular system. VEGFR1 is required for the recruitment of haematopoietic precursors and migration of monocytes and macrophages, whereas VEGFR2 and VEGFR3 are essential for the functions of vascular endothelial and lymphendothelial cells, respectively. Recent insights have shed light onto VEGFR signal transduction and the interplay between different VEGFRs and VEGF co-receptors in development, adult physiology and disease.

VEGF receptor signalling - in control of vascular function.

New blood vessel formation (angiogenesis) is a fundamental event in the process of tumor growth and metastatic dissemination. Hence, the molecular basis of tumor angiogenesis has been of keen interest in the field of cancer research. The vascular endothelial growth factor (VEGF) pathway is well established as one of the key regulators of this process. The VEGF/ VEGF-receptor axis is composed of multiple ligands and receptors with overlapping and distinct ligand-receptor binding specificities, cell-type expression, and function. Activation of the VEGF-receptor pathway triggers a network of signaling processes that promote endothelial cell growth, migration, and survival from pre-existing vasculature. In addition, VEGF mediates vessel permeability, and has been associated with malignant effusions. More recently, an important role for VEGF has emerged in mobilization of endothelial progenitor cells from the bone marrow to distant sites of neovascularization. The well-established role of VEGF in promoting tumor angiogenesis and the pathogenesis of human cancers has led to the rational design and development of agents that selectively target this pathway. Studies with various anti-VEGF/VEGF-receptor therapies have shown that these agents can potently inhibit angiogenesis and tumor growth in preclinical models. Recently, an anti-VEGF antibody (bevacizumab), when used in combination with chemotherapy, was shown to significantly improve survival and response rates in patients with metastatic colorectal cancer and thus, validate VEGF pathway inhibitors as an important new treatment modality in cancer therapy.

Role of the Vascular Endothelial Growth Factor Pathway in Tumor Growth and Angiogenesis

The 13C-NMR chemical shifts of 112 sterols (4-demethyl-, 4-monomethyl-, and 4, 4-dimethylsterols) and triterpene alcohols, most of which are the naturally occurring ones, are listed and a number of methods for signal assignment are explained. The utility of 13C-NMR spectral analysis for the structure elucidation of these compounds is discussed.

https://www.jstage.jst.go.jp/article/jos1956/36/5/36_5_301/_pdf

13C-NMR Spectra of Sterols and Triterpene Alcohols

24-Methylene-25-methylcycloartanol and 24α-ethyl-5α-cholestan-3α-ol from Neolitsea sericea

Occurrence of 24-ethyl-Δ5- and 24-ethyl-Δ7-sterols as c-24 epimerics mixtures in seeds of Cucumis sativus

Transplantation of dedifferentiated fat cell-derived micromass pellets contributed to cartilage repair in the rat osteochondral defect model.

Background: Previous studies have shown that oxidative stress plays an important role in coronary heart disease. Polymorphisms in key enzymes that regulate oxidative stress may play a role in atherogenicity and were investigated in this study. Material/Methods: One hundred and forty-three patients with angiographically proven coronary artery disease were studied. The effect of the C242T polymorphism of the p22phox gene, an essential component of the NADH/NADPH oxidase, and glutathione-S-transferase T1, M1 and P1 polymorphisms on plasma MDA-LDL, soluble CD40 ligand, E-selectin and soluble ICAM1 levels was determined. Genotyping of the p22 phox C242T polymorphism was performed by RFLP analysis, and GSTT1, GSTM1 and GSTP1 genotypes were determined using a multiplex PCR assay. The MDA-LDL, sCD40L, E-selectin and sICAM1 levels were determined using ELISA Results: Patients with the TT or TC genotype of the p22 phox C242T polymorphism had significantly higher plasma MDA-LDL levels compared to those of the CC genotype. Plasma E-selectin and soluble ICAM1 levels were significantly higher in the TT or TC genotype compared to that of the CC genotype. In GSTT1+ patients, plasma MDA-LDL levels were significantly higher than those of GSIT1- patients. Conclusions: Genetic polymorphism of the p22 phox gene had a significant effect on plasma lipid peroxidation and endothelial function through oxidative stress. The results of this study confirm the effect of NADH/NADPH oxidase on atherogenecity.

Influence of genetic polymorphisms in oxidative stress related genes and smoking on plasma MDA-LDL, soluble CD40 ligand, E-selectin and soluble ICAM1 levels in patients with coronary artery disease.

Taro Matsumoto

Papers

13C-NMR Spectra of Sterols and Triterpene Alcohols

24-Methylene-25-methylcycloartanol and 24α-ethyl-5α-cholestan-3α-ol from Neolitsea sericea

Occurrence of 24-ethyl-Δ5- and 24-ethyl-Δ7-sterols as c-24 epimerics mixtures in seeds of Cucumis sativus

Transplantation of dedifferentiated fat cell-derived micromass pellets contributed to cartilage repair in the rat osteochondral defect model.

Influence of genetic polymorphisms in oxidative stress related genes and smoking on plasma MDA-LDL, soluble CD40 ligand, E-selectin and soluble ICAM1 levels in patients with coronary artery disease.