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The angiogenic activity of VEGF manifests both by itself and in the synergism with other regulators of Angiogenesis, (process involving the growth of new blood vessels from pre-existing vessels). The synthesis of VEGF is inducible and depends on many factors, in particular, on hypoxia (deficiency of oxygen).
Furthermore, its activity VEGF manifests in the synergism with other Cytokines. For example, as the "positive" regulators of Angiogenesis (process involving the growth of new blood vessels from pre-existing vessels), are considered aFGF, bFGF, TGF-a, TGF-b, HGF, TNF-A, IL-8, and "negative" influence on the regulation of this process render thrombospondins (TSP - proteins with with antiangiogenic abilities), growth-promoting hormones, angiostatin (naturally occurring proteins in the human body that prevents blood vessel growth), vasostatin (peptide involved in inhibition of angiogenesis), and some others.
In the endothelial cells VEGF induces the synthesis of the Von Willebrand factor (vWF - a blood glycoprotein involved in hemostasis (halting of bleeding)). This Cytokine possesses the pro-coagulative activity: is noted its influence on the induction of the synthesis of plasminogen-activators and the inhibitors of the plasminogen-activators of the 1st type. Furthermore, VEGF induces the synthesis of metal proteinase, as well as collagenase, which splits the collagen of the I- III types with the normal physiological conditions.
There is noted the high influence of this protein on an increase in the vascular penetration, which is a critical step in the process of Angiogenesis (the growth of new blood vessels from pre-existing vessels), associated with the tumors and the healing of wounds. With psoriasis it is noted the intensive expression of VEGF and its receptors, which contributes to an improvement in blood supply to the psoriatic plaque, and its further growth with the development of a local topical inflammation. Blocking VEGF or its receptors VEGF-B, VEGF-C and VEGF-D (for example, by monoclonal antibodies) impedes the development of inflammation, ceases proliferating activity. This means that the anti-angiogenic (decreasing the growth of new blood vessels from pre-existing vessels) factors introduce essential correction into the inflammatory reaction. EGCG is an anti-angiogenic (decreasing the growth of new blood vessels from pre-existing vessels) factor, which inhibits both the protein activity of VEGF receptors, and the level of their transcription.
The involvement of Angiogenesis (the growth of new blood vessels from pre-existing vessels) in the development of psoriasis is proven with the discovery of genetic polymorphism with respect to VEGF. In patients with a severe form of psoriasis there is noted the disorder of regulation of VEGF because of the polymorphous versions of receptors of VEGF in the activated keratinocytes (skin cell that make up 95% of the outer layer of the skin and synthesize keratin) of the skin. The blocking of Angiogenesis (process involving the growth of new blood vessels from pre-existing vessels) led to the steadfast and prolonged remission. One additional proof of the importance of anti-angiogenic (decreasing the growth of new blood vessels from pre-existing vessels) therapy with psoriasis is obtained with a study of Retinoids.
Fat-soluble vitamins (Retinoids) are traditionally used for psoriasis treatment.
The mechanism of their anti-psoriatic action was recently explained. Retinoids become biologically active as a result of activation by them: interaction with their nuclear receptors (receptors of retinoic acid), or interacting with the nuclear factor of transcription AP-1.
It is interesting that in the promoter region of VEGF gene there are four AP-1-connecting sites; interaction of Retinoids with AP-1 blocks the expression of VEGF, i.e. Retinoids possess anti-AP-1 and, therefore, anti-VEGF-activity. Thus, Cytokines IL-8, TNF-A and activated by them NF-kB are the main factors, implicated in the development of pro-inflammatory reaction with psoriasis.
Studies on EGCG indicate the blocking of the activities of these Cytokines at all levels of inflammation both at the protein and the transcription levels. EGCG inhibits the TNF-defined activation of NF-kB through the inhibition of IKK. Furthermore, Nuclear factor kB is inhibited also through the blockade of another signal way, induced by IL-1.
In the absence of NF-kB there is disrupted the expression of IL-8, the main chemoattractant of the mono-nuclear leukocytes (lymphocytes) and neutrophils. Blockade of both signal ways is reached because of the unique ability of EGCG to interfere at any level of pro-inflammatory signal cascades. It is shown that EGCG is the inhibitor of IL-1-associated cytoplasmic kinase (IRAK-kinase), activation of IKK, and phosphorylation of the subunit p65 of Nuclear factor kB.
The functional consequence of activities of EGCG is the inhibition of expression of IL-8, which, besides the manifestation of the chemoattractant properties, influences the expression of the factor of an increase in the Vessel Endothelium (VEGF). Thus, EGCG is simultaneously anti-inflammatory and anti-angiogenic (decreasing the growth of new blood vessels from pre-existing vessels) factor, which makes it an attractive candidate for psoriasis treatment.
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