BioAcyl Corp
BioAcyl Corp |
|
 |
 |
 |
|
Hellenthal, K. E. M., Brabenec, L., & Wagner, N.-M. (2022). Regulation and dysregulation of endothelial permeability during systemic inflammation. Cells, 11(12), 1935. Added by: Dr. Enrique Feoli (23/06/2023, 18:06) Last edited by: Dr. Enrique Feoli (23/06/2023, 18:27) |
 |
| Resource type: Journal Article DOI: 10.3390/cells11121935 ID no. (ISBN etc.): 2073-4409 BibTeX citation key: Hellenthal2022 View all bibliographic details  |
Categories: BioAcyl Corp Subcategories: Endothelial permeability Creators: Brabenec, Hellenthal, Wagner Collection: Cells |
Views: 2/98
|
| Abstract |
|
Systemic inflammation can be triggered by infection, surgery, trauma or burns. During systemic inflammation, an overshooting immune response induces tissue damage resulting in organ dysfunction and mortality. Endothelial cells make up the inner lining of all blood vessels and are critically involved in maintaining organ integrity by regulating tissue perfusion. Permeability of the endothelial monolayer is strictly controlled and highly organ-specific, forming continuous, fenestrated and discontinuous capillaries that orchestrate the extravasation of fluids, proteins and solutes to maintain organ homeostasis. In the physiological state, the endothelial barrier is maintained by the glycocalyx, extracellular matrix and intercellular junctions including adherens and tight junctions. As endothelial cells are constantly sensing and responding to the extracellular environment, their activation by inflammatory stimuli promotes a loss of endothelial barrier function, which has been identified as a hallmark of systemic inflammation, leading to tissue edema formation and hypotension and thus, is a key contributor to lethal outcomes. In this review, we provide a comprehensive summary of the major players, such as the angiopoietin-Tie2 signaling axis, adrenomedullin and vascular endothelial (VE-) cadherin, that substantially contribute to the regulation and dysregulation of endothelial permeability during systemic inflammation and elucidate treatment strategies targeting the preservation of vascular integrity.
Added by: Dr. Enrique Feoli Last edited by: Dr. Enrique Feoli |
| Notes |
|
The Angiopoietin/Tie2 Axis and the Relevance of VE-Cadherin in Protecting Vascular IntegrityModulation of the angiopoietin-Tie2 signaling axis during systemic inflammation. Recombinant human angiopoietin 1 (rhAng1), cartilage oligomeric matrix protein (COMP)-angiopoietin 1 (COMP-Ang1), matrilin-1-angiopoietin-1 (MAT-Ang1) and vasculotide are Tie2 agonists with similar action to angiopoietin 1, while peroxisome proliferator–activated receptor-γ (PPAR-γ) agonists upregulate angiopoietin 1 bioavailability. Small interfering RNA (siRNA) against angiopoietin 2 and PPAR-γ agonists reduce angiopoietin 2 expression. AKB-9778 is an antibody directed against vascular endothelial protein tyrosine phosphatase (VE-PTP) and thus indirectly activates Tie2. ABTAA is a novel ANG2-binding and Tie2-activating antibody combining the features of angiopoietin 2 inhibition and Tie2 activation. Tie1 further modulates response at the Tie2 receptor as endothelial cells shed the Tie1 ectodomain leading to Ang2 binding, resulting in Tie2 antagonism and reducing the agonistic activity of Ang1 during inflammation. Mechanistically, these treatment strategies lead to Tie2 receptor agonism, resulting in enhanced vascular barrier function by the PI3K/Akt signaling cascade and anti-inflammation by suppression of transcription factor NF-κB and, thus, of intercellular adhesion molecule (I-CAM) and vascular cell adhesion molecule (V-CAM). Downstream of phosphatidylinositol-3-kinase/protein kinase B (PI3/Akt) activation, there is the GTPase-activating protein 1 (IQGAP1), which activates Rac1 by stabilizing it in its active GTP-bound form, whereas Rho GTPase-activating protein p190RhoGAP converts RhoA into its inactive state. These steps promote an increase in cortical actin that strengthens the cytoskeleton and thus the vascular barrier function, whereas Tie2 activation additionally results in inhibition of Src kinase preventing the phosphorylation and internalization of vascular endothelial-cadherin (VE-cadherin). This figure was created with BioRender.com and adapted from Pariksh SM et al., J Am Soc Nephr 2017 and Wettschureck et al., Physiol Rev 2019 [36,74]. Added by: Dr. Enrique Feoli Last edited by: Dr. Enrique Feoli |
