Page last updated: 2024-10-24

regulation of vascular endothelial growth factor signaling pathway

Definition

Target type: biologicalprocess

Any process that modulates the frequency, rate or extent of vascular endothelial growth factor signaling pathway. [GOC:TermGenie]

Vascular endothelial growth factor (VEGF) signaling is a complex and tightly regulated process that plays a critical role in angiogenesis, the formation of new blood vessels. This process is essential for normal development, tissue repair, and wound healing. However, dysregulation of VEGF signaling can contribute to various diseases, including cancer, diabetic retinopathy, and rheumatoid arthritis.

VEGF signaling is initiated by the binding of VEGF to its cognate receptors, VEGFR1 (FLT1) and VEGFR2 (KDR). These receptors are tyrosine kinase receptors that upon ligand binding undergo dimerization and autophosphorylation. Phosphorylation of the receptors creates docking sites for downstream signaling molecules, including phospholipase C-gamma (PLC-gamma), phosphoinositide 3-kinase (PI3K), and Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2).

Activation of PLC-gamma leads to the production of diacylglycerol (DAG) and inositol trisphosphate (IP3), which activate protein kinase C (PKC) and release calcium from intracellular stores, respectively. PKC and calcium signaling contribute to cell survival, proliferation, and migration.

Activation of PI3K results in the production of phosphatidylinositol-3,4,5-trisphosphate (PIP3), which activates Akt (protein kinase B) and other downstream effectors. Akt signaling promotes cell survival, proliferation, and angiogenesis.

Activation of SHP2 leads to the activation of Ras, a small GTPase. Ras activation activates the mitogen-activated protein kinase (MAPK) pathway, which promotes cell proliferation and migration.

VEGF signaling also activates other signaling pathways, including the Ras-related C3 botulinum toxin substrate 1 (Rac1) and Rho GTPase pathways, which regulate cytoskeletal rearrangements and cell migration.

Regulation of VEGF signaling is crucial for maintaining vascular homeostasis. Several mechanisms contribute to the regulation of this pathway, including:

* **VEGF expression:** VEGF expression is tightly regulated by various factors, including hypoxia, growth factors, and cytokines. Hypoxia is a potent inducer of VEGF expression, and this induction is mediated by the hypoxia-inducible factor (HIF) pathway.
* **VEGF receptor expression:** The expression of VEGF receptors is also regulated by various factors, including growth factors, cytokines, and hormones.
* **Receptor phosphorylation:** The phosphorylation of VEGF receptors is regulated by tyrosine kinases and phosphatases, which can modulate receptor activity.
* **Internalization and degradation:** VEGF receptors undergo internalization and degradation, which can downregulate receptor signaling.
* **Negative feedback loops:** VEGF signaling can activate negative feedback loops that inhibit further signaling. For example, VEGF can induce the expression of soluble VEGF receptors (sVEGFRs), which act as decoy receptors that bind to VEGF and prevent it from activating cell surface receptors.

Dysregulation of VEGF signaling can contribute to various pathological conditions. Overactivation of VEGF signaling can lead to excessive angiogenesis, which is associated with cancer, diabetic retinopathy, and rheumatoid arthritis. Conversely, decreased VEGF signaling can lead to impaired angiogenesis, which can contribute to ischemia and tissue damage.

In summary, VEGF signaling is a complex and tightly regulated process that plays a critical role in angiogenesis and vascular homeostasis. Understanding the mechanisms that regulate this pathway is essential for developing new therapies for diseases associated with dysregulated VEGF signaling.'
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Proteins (1)

ProteinDefinitionTaxonomy
Protein tyrosine phosphatase type IVA 3A protein tyrosine phosphatase type IVA 3 that is encoded in the genome of human. [PRO:DNx, UniProtKB:O75365]Homo sapiens (human)

Compounds (5)

CompoundDefinitionClassesRoles
emodinemodin : A trihydroxyanthraquinone that is 9,10-anthraquinone which is substituted by hydroxy groups at positions 1, 3, and 8 and by a methyl group at position 6. It is present in the roots and barks of numerous plants (particularly rhubarb and buckthorn), moulds, and lichens. It is an active ingredient of various Chinese herbs.

Emodin: Purgative anthraquinone found in several plants, especially RHAMNUS PURSHIANA. It was formerly used as a laxative, but is now used mainly as a tool in toxicity studies.
trihydroxyanthraquinoneantineoplastic agent;
laxative;
plant metabolite;
tyrosine kinase inhibitor
pentamidinepentamidine : A diether consisting of pentane-1,5-diol in which both hydroxyl hydrogens have been replaced by 4-amidinophenyl groups. A trypanocidal drug that is used for treatment of cutaneous leishmaniasis and Chagas disease.

Pentamidine: Antiprotozoal agent effective in trypanosomiasis, leishmaniasis, and some fungal infections; used in treatment of PNEUMOCYSTIS pneumonia in HIV-infected patients. It may cause diabetes mellitus, central nervous system damage, and other toxic effects.
aromatic ether;
carboxamidine;
diether
anti-inflammatory agent;
antifungal agent;
calmodulin antagonist;
chemokine receptor 5 antagonist;
EC 2.3.1.48 (histone acetyltransferase) inhibitor;
NMDA receptor antagonist;
S100 calcium-binding protein B inhibitor;
trypanocidal drug;
xenobiotic
2-[[5-(3-chlorophenyl)-4-prop-2-enyl-1,2,4-triazol-3-yl]thio]-1-(3,4-dihydroxyphenyl)ethanonearomatic ketone
ginkgetinginkgetin : A biflavonoid that is the 7,4'-dimethyl ether derivative of amentoflavone. Isolated from Ginkgo biloba and Dioon, it exhibits anti-HSV-1, antineoplastic and inhibitory activities towards arachidonate 5-lipoxygenase and cyclooxygenase 2.

ginkgetin: from Cephalotaxus drupacea; biflavone; active against HSV-1; structure given in first source
biflavonoid;
hydroxyflavone;
methoxyflavone;
ring assembly
anti-HSV-1 agent;
antineoplastic agent;
cyclooxygenase 2 inhibitor;
EC 1.13.11.34 (arachidonate 5-lipoxygenase) inhibitor;
metabolite
sciadopitysinsciadopitysin : A biflavonoid that is a 7, 4', 4'''-trimethyl ether derivative of amentoflavone.

sciadopitysin: biflavonoid from Taxus celebica & Ginkgo biloba
biflavonoid;
hydroxyflavone;
methoxyflavone;
ring assembly
bone density conservation agent;
platelet aggregation inhibitor