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Thus, VEGFD induced endothelial cell Glimepiride migration but was not able to stimulate their proliferation.Knowledge of peculiarities of the angiogenic effect of a particular growth factor of this family might be important in development on their basis of different drug preparations that can be used for stimulation of angiogenesis or for inhibition of neoangiogenesis in tumors.In adults, VEGFR is expressed mainly on endothelium of lymphatic vessels.The disturbance of the intracellular signaling cascade associated with this Glimepiride Receptor selectively affects lymphangiogenesis. Receptor VEGFR does not interact with VEGFA, its ligands being two other members of this family, VEGFC and VEGFD. Similarly to the key role played by VEGFA in blood vessel growth, VEGFC is an important regulator of lymphangiogenesis.VEGFD also exhibits lymphangiogenic activity but is not critical for development of the lymphatic system. Primary VEGFC and VEGFD protein products later undergo posttranslational proteolytic processing resulting in cleavage of the NH region containing the signal peptide, and a significant part of the COOH region.As a result, the main part of the mature protein consists of a region homologous to VEGFA. Both VEGFC and VEGFD are ligands for receptors VEGFR and VEGFR, and the affinity of their binding to a particular receptor changes during proteolytic maturation.Immature forms of VEGFC and VEGFD, generated during partial processing, bind only to VEGFR, whereas mature forms of these proteins retain their ability to interact with VEGFR and simultaneously activate VEGFR as well.Due to this peculiarity, the biological effect of growth factors VEGFC and VEGFD can be ambiguous: they are able to activate both lymphangiogenesis via interaction with VEGFR and angiogenesis by stimulation of VEGFR.Moreover, it was shown that VEGFR was able to form heterodimers with VEGFR. Thus, the biological consequences of VEGFC and VEGFD activation can be quite ambiguous and depend on many factors, including quantitative ratios of receptors VEGFR and VEGFR in the tissue.Changes in the ratio of VEGFR receptors can be observed during tumor progression.In the course of investigation of VEGFR gene receptor expression in benign and malignant human thyroid tumors, we have found increased amounts of the corresponding mRNA in adenomas compared to that in normal thyroid tissue, whereas expression of this gene in adenocarcinomas was much more heterogeneous and on the whole it was decreased. We obtained similar data during investigation of VEGFR and VEGFR gene expression in samples of human bladder cancer.Expression of both genes at early stages of tumor progression was rather high.At later stages, expression of VEGFR remained practically at the same level, whereas expression of VEGFR, as in the case of thyroid tumors, became heterogeneous, and the total level of expression of this gene was decreased.It turned out that for the interaction of VEGFA with these receptors the presence of a fragment encoded by the seventh exon is of fundamental significance because isoform VEGF devoid of this fragment did not bind the newly found receptors.It became clear later that transmembrane neuropilin receptors, whose ligands are members of the semaphorine family involved in nerve cell regulation, correspond to these newly found receptors.

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