Permeability of the Endothelial Barrier: Identifying and Reconciling Controversies

Claesson‐Welsh, Lena; Dejana, Elisabetta; McDonald, Donald M.

doi:10.1016/j.molmed.2020.11.006

Cited by 384 publications

(361 citation statements)

References 142 publications

(176 reference statements)

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“…In addition to the loss of cell-to-cell junctions, uremic serum also induces cytoskeleton remodeling and changes in cell morphology (Peng et al, 2012a;Maciel et al, 2018;Vila Cuenca et al, 2019). The main consequences of structural endothelial damage are the increased vascular permeability and vessel leakage (Chistiakov et al, 2015;Claesson-Welsh et al, 2020), several studies have shown that PCS, IS, AGEs and uremic serum increase endothelial barrier permeability (Hirose et al, 2010;Maciel et al, 2018;Assefa et al, 2019;Vila Cuenca et al, 2019;Chen et al, 2020).…”

Section: Uremic Toxins In Endothelial Dysfunctionmentioning

confidence: 99%

Uremic Toxins: An Alarming Danger Concerning the Cardiovascular System

et al. 2021

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The kidneys and heart share functions with the common goal of maintaining homeostasis. When kidney injury occurs, many compounds, the so-called “uremic retention solutes” or “uremic toxins,” accumulate in the circulation targeting other tissues. The accumulation of uremic toxins such as p-cresyl sulfate, indoxyl sulfate and inorganic phosphate leads to a loss of a substantial number of body functions. Although the concept of uremic toxins is dated to the 1960s, the molecular mechanisms capable of leading to renal and cardiovascular injuries are not yet known. Besides, the greatest toxic effects appear to be induced by compounds that are difficult to remove by dialysis. Considering the close relationship between renal and cardiovascular functions, an understanding of the mechanisms involved in the production, clearance and overall impact of uremic toxins is extremely relevant for the understanding of pathologies of the cardiovascular system. Thus, the present study has as main focus to present an extensive review on the impact of uremic toxins in the cardiovascular system, bringing the state of the art on the subject as well as clinical implications related to patient’s therapy affected by chronic kidney disease, which represents high mortality of patients with cardiac comorbidities.

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Section: Uremic Toxins In Endothelial Dysfunctionmentioning

confidence: 99%

Uremic Toxins: An Alarming Danger Concerning the Cardiovascular System

et al. 2021

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“…Retinal vascular diseases are characterized by aberrant angiogenesis accompanying the dysregulated proliferation and migration of endothelial cells (ECs), which causes vitreous hemorrhages and, ultimately, tractional retinal detachment [1,2]. In these settings, the disruption of EC-EC junctions in preexisting and newly formed blood vessels causes plasma extravasation and retinal edema [3,4]. While various cytokines have been implicated in these pathologies, vascular endothelial growth factor (VEGF) A is a major driver of both angiogenesis and vascular hyperpermeability, which has been corroborated with the therapeutic potency of anti-VEGF agents in diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Rho GTPases in Retinal Vascular Diseases

Fukushima

2021

IJMS

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The Rho family of small GTPases (Rho GTPases) act as molecular switches that transduce extrinsic stimuli into cytoskeletal rearrangements. In vascular endothelial cells (ECs), Cdc42, Rac1, and RhoA control cell migration and cell–cell junctions downstream of angiogenic and inflammatory cytokines, thereby regulating vascular formation and permeability. While these Rho GTPases are broadly expressed in various types of cells, RhoJ is enriched in angiogenic ECs. Semaphorin 3E (Sema3E) releases RhoJ from the intracellular domain of PlexinD1, by which RhoJ induces actin depolymerization through competition with Cdc42 for their common effector proteins. RhoJ further mediates the Sema3E-induced association of PlexinD1 with vascular endothelial growth factor receptor (VEGFR) 2 and the activation of p38. Upon stimulation with VEGF-A, RhoJ facilitates the formation of a holoreceptor complex comprising VEGFR2, PlexinD1, and neuropilin-1, leading to the prevention of VEGFR2 degradation and the maintenance of intracellular signal transduction. These pleiotropic roles of RhoJ are required for directional EC migration in retinal angiogenesis. This review highlights the latest insights regarding Rho GTPases in the field of vascular biology, as it will be informative to consider their potential as targets for the treatment of aberrant angiogenesis and hyperpermeability in retinal vascular diseases.

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“…A major finding of our work is that aPC stimulates SphK1 activity via β-arr2 but not Dlv-2, indicating that unique β-arr2-driven cytoprotective signaling pathways exist. Previous studies showed that aPC promotes barrier stabilization and protection against thrombin and vascular endothelial growth factor (VEGF)-induced barrier leakage (Claesson-Welsh et al, 2020; Rahimi, 2017). We discovered that aPC-activated PAR1 signals preferentially via β-arr2 and not heterotrimeric G proteins to confer protection against thrombin-induced barrier disruption (Soh & Trejo, 2011).…”

Section: Discussionmentioning

confidence: 99%

aPC/PAR1 confers endothelial anti-apoptotic activity via a discrete β-arrestin-2 mediated SphK1-S1PR1-Akt signaling axis

Molinar‐Inglis

Nicholas

et al. 2021

Preprint

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Endothelial dysfunction is associated with multiple vascular diseases and lacks effective treatment options. Activated Protein C (aPC) is a promising biotherapeutic that signals via protease-activated receptor-1 (PAR1) to promote diverse cytoprotective responses, including endothelial barrier stabilization, anti-inflammatory, and anti-apoptotic activities, which require specific co-receptors. We show that aPC-activated PAR1 signals preferentially via β-arrestin-2 (β-arr2) and dishevelled-2 (Dvl-2) scaffolds rather than heterotrimeric G proteins. However, the mechanisms by which aPC/PAR1 elicits diverse cytoprotective responses are poorly defined. Here we define a novel β-arrestin-2-mediated sphingosine kinase-1 (SphK1)-sphingosine-1-phosphate receptor-1 (S1PR1)-Akt signaling axis that confers aPC/PAR1-mediated protection against cell death. aPC stimulates the phosphorylation, translocation, and activation of SphK1 and is dependent on β-arrestin-2 and not Dvl-2. Moreover, aPC/PAR1 markedly increases S1PR1-caveolin-1 co-association, although both receptors co-existed in caveolin-1 enriched microdomains before aPC stimulation. These studies reveal that aPC/PAR1 cytoprotective responses are mediated by discrete β-arr2-driven signaling pathways modulated by co-receptors localized in caveolae.

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Permeability of the Endothelial Barrier: Identifying and Reconciling Controversies

Cited by 384 publications

References 142 publications

Uremic Toxins: An Alarming Danger Concerning the Cardiovascular System

Uremic Toxins: An Alarming Danger Concerning the Cardiovascular System

Rho GTPases in Retinal Vascular Diseases

aPC/PAR1 confers endothelial anti-apoptotic activity via a discrete β-arrestin-2 mediated SphK1-S1PR1-Akt signaling axis

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