negative regulation of endothelial cell chemotaxis

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of endothelial cell chemotaxis. [GOC:BHF]

Negative regulation of endothelial cell chemotaxis involves a complex interplay of signaling pathways that suppress the directed migration of endothelial cells towards chemoattractants. This process is crucial for maintaining vascular integrity and preventing aberrant angiogenesis. Here's a detailed breakdown:

1. **Chemoattractant Sensing:** Endothelial cells express receptors on their surface that bind to chemoattractants, such as vascular endothelial growth factor (VEGF) and chemokines. This binding initiates intracellular signaling cascades.

2. **Inhibition of Signaling Cascades:** Negative regulation can occur at multiple points within these signaling pathways:
* **Receptor Downregulation:** Endocytosis of receptors, internalization and degradation, or desensitization through phosphorylation can reduce the number of available receptors on the cell surface.
* **Inhibitory Proteins:** Specific proteins, like Sprouty proteins, can bind to and inhibit receptor tyrosine kinases involved in chemotaxis signaling, like VEGFR2.
* **Phosphatases:** Enzymes like SHP2 dephosphorylate signaling proteins, effectively shutting down the signal transduction cascade.
* **Second Messenger Modulation:** Negative regulation can occur at the level of second messengers, such as cAMP or calcium, by modulating their production, degradation, or downstream signaling.

3. **Cytoskeletal Rearrangement Inhibition:** Chemotaxis requires dynamic cytoskeletal rearrangements, primarily involving actin polymerization and depolymerization. Negative regulators can:
* **Inhibit Actin Polymerization:** Proteins like cofilin or gelsolin can sever actin filaments, inhibiting polymerization and preventing the formation of lamellipodia and filopodia, structures crucial for cell migration.
* **Promote Actin Depolymerization:** Proteins like ADF/cofilin can promote depolymerization of existing actin filaments, reducing the overall available actin pool for assembly.

4. **Adhesion Modulation:** Endothelial cells adhere to the extracellular matrix (ECM) via integrins, and this adhesion is regulated during chemotaxis. Negative regulators can:
* **Downregulate Integrin Expression:** Reducing the number of integrins on the cell surface weakens the cell's adhesion to the ECM.
* **Modulate Integrin Affinity:** Specific proteins can alter the affinity of integrins for their ECM ligands, impacting adhesion strength.

5. **Cell Cycle Regulation:** Cell cycle progression is often coupled to chemotaxis, and negative regulators can:
* **Induce Cell Cycle Arrest:** Stopping cell cycle progression can indirectly suppress chemotaxis by preventing the cell from entering the necessary phase for migration.

6. **Transcriptional Regulation:** Negative regulation can also occur at the level of gene expression. Transcription factors can be activated or inhibited to regulate the expression of genes encoding chemoattractant receptors, signaling proteins, or cytoskeletal components, ultimately affecting the cell's migratory capacity.

7. **Microenvironment Modulation:** Factors in the surrounding microenvironment can also contribute to negative regulation:
* **Matrix Stiffness:** ECM stiffness can influence cell adhesion and migration.
* **Oxygen Tension:** Hypoxia can inhibit endothelial cell chemotaxis.
* **Growth Factors and Cytokines:** Certain growth factors and cytokines, like transforming growth factor-beta (TGF-β), can suppress endothelial cell migration.'
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