positive regulation of endothelial cell chemotaxis by VEGF-activated vascular endothelial growth factor receptor signaling pathway

Definition

Target type: biologicalprocess

The series of molecular signals initiated by the binding of a vascular endothelial growth factor (VEGF) to its receptor on the surface of a cell, which activates or increases the frequency, rate or extent of endothelial cell chemotaxis. [GOC:bf, GOC:BHF, GOC:rl, PMID:21245381]

Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis, the formation of new blood vessels. This process is essential for development, wound healing, and tissue repair. VEGF exerts its effects by binding to its cognate receptor, vascular endothelial growth factor receptor (VEGFR), which is expressed on the surface of endothelial cells, the cells that line blood vessels. Upon binding, VEGFR undergoes a series of conformational changes that activate its intrinsic tyrosine kinase activity. This activation triggers a signaling cascade that ultimately leads to the recruitment and migration of endothelial cells towards the site of VEGF production.

The positive regulation of endothelial cell chemotaxis by VEGF-activated VEGFR signaling pathway involves a complex interplay of various signaling molecules and downstream effectors.

1. **VEGF Binding and Receptor Dimerization:** VEGF binding to VEGFR induces receptor dimerization, bringing together two VEGFR molecules. This dimerization is essential for the activation of the receptor's tyrosine kinase activity.

2. **Tyrosine Kinase Activation and Phosphorylation:** Upon dimerization, the tyrosine kinase domains of VEGFR become activated and phosphorylate specific tyrosine residues on the receptor itself and on other signaling molecules.

3. **Activation of Downstream Signaling Pathways:** Phosphorylated tyrosine residues on VEGFR serve as docking sites for various adaptor proteins and signaling molecules, including phospholipase C-gamma (PLC-gamma), phosphatidylinositol 3-kinase (PI3K), and Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP-2). These proteins are recruited to the activated VEGFR and initiate downstream signaling pathways.

4. **Activation of PI3K/Akt Pathway:** PI3K is activated by VEGFR and catalyzes the phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 acts as a second messenger and recruits AKT, a serine/threonine kinase, to the plasma membrane. AKT is then phosphorylated and activated. The PI3K/Akt pathway plays a crucial role in promoting cell survival, growth, and migration.

5. **Activation of PLC-gamma Pathway:** PLC-gamma is also activated by VEGFR and hydrolyzes PIP2 into diacylglycerol (DAG) and inositol triphosphate (IP3). DAG activates protein kinase C (PKC), which can further contribute to cell migration and survival. IP3 mobilizes intracellular calcium, which is essential for cytoskeletal remodeling and cell motility.

6. **Activation of Ras/MAPK Pathway:** The VEGFR signaling pathway can also activate the Ras/mitogen-activated protein kinase (MAPK) pathway. Ras is a small GTPase that is activated by the SHP-2 phosphatase. Activated Ras activates the Raf-MEK-ERK cascade, which leads to the phosphorylation of transcription factors and ultimately promotes cell proliferation, survival, and migration.

7. **Cytoskeletal Remodeling and Cell Migration:** The activation of these signaling pathways leads to a series of downstream events, including cytoskeletal remodeling, changes in cell adhesion, and the formation of lamellipodia, which are finger-like protrusions that help cells move. These events are essential for the directed migration of endothelial cells towards the site of VEGF production.

8. **Positive Feedback Loop:** The activation of VEGFR signaling pathway can also lead to the upregulation of VEGF expression, creating a positive feedback loop that amplifies the angiogenic response.

In summary, the positive regulation of endothelial cell chemotaxis by VEGF-activated VEGFR signaling pathway involves a complex series of events that ultimately lead to the directed migration of endothelial cells towards the site of VEGF production. This process is essential for angiogenesis, which is a vital process for development, wound healing, and tissue repair.
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