negative regulation of establishment of endothelial barrier

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of establishment of endothelial barrier. [GO_REF:0000058, GOC:als, GOC:TermGenie, PMID:24851274]

Negative regulation of establishment of endothelial barrier is a complex process that involves the coordinated action of various cellular signaling pathways and protein interactions. The endothelial barrier, formed by tight junctions and adherens junctions between endothelial cells, plays a crucial role in maintaining vascular integrity and regulating the passage of fluids, nutrients, and immune cells between the blood and surrounding tissues.

**Key Mechanisms Involved:**

1. **Regulation of Cell-Cell Adhesion:** The establishment of the endothelial barrier is largely dependent on the formation and maintenance of cell-cell junctions. These junctions involve specialized transmembrane proteins, such as cadherins and claudins, which mediate adhesion and tight seal formation between adjacent endothelial cells. Negative regulation of this process can occur through:
- **Downregulation of junctional protein expression:** Decreasing the levels of cadherins, claudins, or other junctional proteins can weaken the integrity of the barrier.
- **Disruption of junctional protein interactions:** Factors that interfere with the proper assembly or stability of junctional complexes can also compromise barrier function.
- **Activation of signaling pathways that promote junctional disassembly:** Certain signaling pathways, such as the RhoA pathway, can trigger the breakdown of cell-cell junctions, leading to barrier disruption.

2. **Control of Cell Shape and Polarity:** Endothelial cells exhibit a highly polarized structure, with distinct apical and basolateral domains. Maintaining this polarity is essential for barrier function. Disrupting cell polarity can lead to:
- **Loss of apical-basolateral differentiation:** This can impair the proper localization of junctional proteins and other barrier-related molecules.
- **Increased permeability:** Loss of polarity can lead to a more permeable barrier, allowing for the passage of larger molecules and cells.

3. **Regulation of Cytoskeletal Dynamics:** The cytoskeleton, a network of protein filaments within cells, plays a critical role in maintaining cell shape, adhesion, and barrier integrity. Negative regulation of cytoskeletal dynamics can occur through:
- **Depolymerization of actin filaments:** Actin filaments are crucial for the formation and stabilization of cell-cell junctions. Their depolymerization weakens the barrier.
- **Disruption of microtubule organization:** Microtubules are involved in the transport of proteins and vesicles necessary for barrier function. Disrupting microtubule organization can impair these processes.

4. **Modulation of Signaling Pathways:** Various signaling pathways contribute to the regulation of the endothelial barrier. Negative regulation can occur through:
- **Activation of pro-inflammatory pathways:** Inflammatory mediators, such as TNF-alpha and IL-1beta, can trigger signaling pathways that promote barrier disruption.
- **Inhibition of barrier-protective pathways:** Some signaling pathways, such as the PI3K/Akt pathway, promote barrier formation and stability. Inhibiting these pathways can weaken the barrier.

5. **Influence of Extracellular Matrix:** The extracellular matrix (ECM) surrounding endothelial cells provides structural support and influences cell behavior. Factors that disrupt ECM organization or composition can negatively affect barrier function.

**Consequences of Negative Regulation:**

Negative regulation of the establishment of the endothelial barrier can lead to a variety of pathological consequences, including:
- **Increased vascular permeability:** This can lead to edema (fluid accumulation) and tissue swelling.
- **Inflammation:** Barrier disruption can allow for the passage of immune cells and inflammatory mediators, contributing to tissue inflammation.
- **Tissue damage:** Increased permeability and inflammation can damage tissues, leading to organ dysfunction.
- **Disease progression:** Negative regulation of the endothelial barrier is implicated in the pathogenesis of various diseases, including sepsis, cancer, and diabetes.

**Conclusion:**

Negative regulation of the establishment of the endothelial barrier is a complex process involving multiple cellular mechanisms. Understanding these mechanisms is crucial for developing therapeutic strategies to prevent or reverse barrier dysfunction in various pathological conditions.'
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Proteins (2)

Compounds (19)