negative regulation of vascular endothelial growth factor signaling pathway

Definition

Target type: biologicalprocess

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

Negative regulation of vascular endothelial growth factor (VEGF) signaling pathway is a crucial biological process that controls the formation and development of blood vessels, known as angiogenesis. VEGF, a potent growth factor, plays a critical role in promoting angiogenesis by binding to its receptors, VEGFR1 and VEGFR2, on endothelial cells. This binding activates downstream signaling cascades, leading to cell proliferation, migration, and survival, ultimately resulting in new blood vessel formation.

The negative regulation of this pathway is essential for maintaining vascular homeostasis, preventing excessive angiogenesis, and controlling tumor growth. This regulation is achieved through a variety of mechanisms that target different stages of the VEGF signaling cascade.

**1. Inhibition of VEGF Production:**
- **Hypoxia-inducible factor (HIF) regulation:** Under hypoxic conditions, HIFs are stabilized and stimulate VEGF production. Factors that inhibit HIF activation, such as prolyl hydroxylases, can decrease VEGF levels.
- **Growth factors and cytokines:** Certain growth factors and cytokines, such as transforming growth factor-beta (TGF-β), can inhibit VEGF expression.
- **MicroRNAs:** Specific microRNAs can target and degrade VEGF mRNA, reducing its production.

**2. Blocking VEGF Binding:**
- **Soluble VEGF receptors:** Soluble forms of VEGFRs (sVEGFRs), generated through proteolytic cleavage, can bind to VEGF and prevent its interaction with cell surface receptors.
- **VEGF traps:** Engineered proteins that specifically bind to VEGF and block its activity.

**3. Disrupting Receptor Signaling:**
- **Tyrosine kinase inhibitors:** These molecules target the tyrosine kinase domains of VEGFRs, inhibiting their phosphorylation and downstream signaling.
- **Internalization and degradation:** Receptor-mediated endocytosis of VEGFRs can lead to their lysosomal degradation.
- **Negative feedback loops:** Activation of VEGF signaling can trigger feedback mechanisms that downregulate receptor activity, such as the induction of inhibitory proteins.

**4. Targeting Downstream Signaling:**
- **MAPK pathway inhibition:** Inhibition of the mitogen-activated protein kinase (MAPK) pathway, a key downstream effector of VEGF signaling, can suppress angiogenesis.
- **PI3K/AKT pathway inhibition:** Blocking the phosphoinositide 3-kinase (PI3K)/AKT pathway, another important downstream pathway, can reduce cell survival and proliferation.

**5. Regulation of Endothelial Cell Function:**
- **Anti-angiogenic factors:** Various proteins, such as thrombospondin-1 and endostatin, directly inhibit endothelial cell growth and migration.
- **Matrix metalloproteinase (MMP) inhibitors:** MMPs play a role in remodeling the extracellular matrix and promoting angiogenesis. MMP inhibitors can suppress angiogenesis by affecting ECM degradation.

In summary, the negative regulation of VEGF signaling pathway is a complex process involving a diverse array of mechanisms that target different stages of the pathway. This intricate regulation is crucial for maintaining vascular health, controlling angiogenesis, and preventing uncontrolled vascular growth associated with various diseases, including cancer.'
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