Roche Protease Inhibitor

Furthermore, the manner in which this knowledge is being exploited to regulate angiogenesis will be discussed.Angiogenesis denotes the formation of new blood vessels from preexisting vessels.Physiological angiogenesis, which is required for embryonic development, wound healing and the menstrual cycle, is characterized by tight regulation both spatially and temporally.Angiogenic factors, such as fibroblast growth factors, stimulate endothelial cells to secrete several proteases and plasminogen activators, resulting in the degradation of the vessel basement membrane, which in turn allows cells to invade the surrounding matrix.The cells migrate, proliferate and eventually differentiate to form a new, lumencontaining vessel.Finally, the endothelial cells deposit a new basement membrane and secrete growth factors, such as plateletderived growth factor, which attract supporting cells such as pericytes, ensuring the stability of the new vessel.Binding of FGF results in receptor dimerization and the phosphorylation of specific tyrosine residues within the intracellular domain of the receptor. Several pathological conditions, such as tumour progression, rheumatoid arthritis and diabetes, are characterized by excessive angiogenesis where vessels develop in an uncontrolled or disorganized manner.Thus, the dormant cancer in situ can expand once it has acquired the ability to disturb the balance between the production of stimulatory factors and the production of inhibitory factors, thereby promoting the angiogenic switch.Many different tumour cells secrete VEGF, the expression of which is regulated by hypoxia.Recently, novel antiangiogenic agents have been developed that inhibit the action of FGF and VEGF.Several of these compounds are now in clinical trials and might offer hope in the treatment and management of several diseases.At present, the FGF family is known to contain at least factors, which are identical in their primary amino acid sequences.The apparent lack of regulated FGF export has been an obstacle in the wide acceptance of a crucial role for FGF in angiogenesis; however, there are several working models for alternative modes of transport out of the cell rather than via the classical secretory apparatus.Alternative splicing of the FGFR mRNA generates receptor variants, which display a range of receptorligand interactions.Disruption of the genes encoding FGFR or FGFR leads to embryonal death before gastrulation. This early lethality has made it impossible to define specifically the role of these FGF receptors in the later stages of development and in angiogenesis.However, recent work using adenovirusmediated expression of dominantnegative FGFR in mouse embryos has shown that FGFR is required for the development and maintenance of the vasculature in the embryo.By contrast, inactivation of the gene encoding FGF results in mice that are morphologically normal but display decreased vascular tone and low blood pressure.When reconciled with the receptor knockout data, this suggests redundancy in the FGF family.Disruption of the gene encoding FGFR results in mice with skeletal abnormalities, whereas the result of inactivation of the gene encoding FGFR has not been reported.Receptor dimerization results in the intermolecular autophosphorylation of specific tyrosine residues within the dimeric complex.Several autophosphorylation sites have been identified in FGFR. VEGF ligands and receptors VEGF was initially termed vascular permeability factor because of its ability to induce vascular leakage.The VEGF family currently comprises six members: VEGFA, VEGFB, VEGFC, VEGFD and the orf parapox virus VEGF, referred to as VEGFE.

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