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Endothelial Activation: The Ang/Tie Axis in Sepsis.

ABSTRACT: Sepsis, a dysregulated host response to infection that causes life-threatening organ dysfunction, is a highly heterogeneous syndrome with no specific treatment. Although sepsis can be caused by a wide variety of pathogenic organisms, endothelial dysfunction leading to vascular leak is a common mechanism of injury that contributes to the morbidity and mortality associated with the syndrome. Perturbations to the angiopoietin (Ang)/Tie2 axis cause endothelial cell activation and contribute to the pathogenesis of sepsis. In this review, we summarize how the Ang/Tie2 pathway is implicated in sepsis and describe its prognostic as well as therapeutic utility in life-threatening infections.

SUBMITTER: Leligdowicz A

PROVIDER: S-EPMC5928262 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Endothelial Activation: The Ang/Tie Axis in Sepsis.

Leligdowicz Aleksandra A Richard-Greenblatt Melissa M Wright Julie J Crowley Valerie M VM Kain Kevin C KC

Frontiers in immunology 20180424

Sepsis, a dysregulated host response to infection that causes life-threatening organ dysfunction, is a highly heterogeneous syndrome with no specific treatment. Although sepsis can be caused by a wide variety of pathogenic organisms, endothelial dysfunction leading to vascular leak is a common mechanism of injury that contributes to the morbidity and mortality associated with the syndrome. Perturbations to the angiopoietin (Ang)/Tie2 axis cause endothelial cell activation and contribute to the p ...[more]

PMID: 29740443

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Sulfated glycans engage the Ang-Tie pathway to regulate vascular development.

Project description:The angiopoietin (Ang)-Tie pathway is essential for the proper maturation and remodeling of the vasculature. Despite its importance in disease, the mechanisms that control signal transduction through this pathway are poorly understood. Here, we demonstrate that heparan sulfate glycosaminoglycans (HS GAGs) regulate Ang-Tie signaling through direct interactions with both Ang ligands and Tie1 receptors. HS GAGs formed ternary complexes with Ang1 or Ang4 and Tie2 receptors, resulting in potentiation of endothelial survival signaling. In addition, HS GAGs served as ligands for the orphan receptor Tie1. The HS-Tie1 interaction promoted Tie1-Tie2 heterodimerization and enhanced Tie1 stability within the mature vasculature. Loss of HS-Tie1 binding using CRISPR-Cas9-mediated mutagenesis in vivo led to decreased Tie protein levels, pathway suppression and aberrant retinal vascularization. Together, these results reveal that sulfated glycans use dual mechanisms to regulate Ang-Tie signaling and are important for the development and maintenance of the vasculature.

| S-EPMC8087285 | biostudies-literature

A systems biology model of junctional localization and downstream signaling of the Ang-Tie signaling pathway.

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| S-EPMC8379279 | biostudies-literature

Adiponectin deficiency promotes endothelial activation and profoundly exacerbates sepsis-related mortality.

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Disruption of Ang-1/Tie-2 signaling contributes to the impaired myocardial vascular maturation and angiogenesis in type II diabetic mice.

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Propofol prevents human umbilical vein endothelial cell injury from Ang II-induced apoptosis by activating the ACE2-(1-7)-Mas axis and eNOS phosphorylation.

Project description:Angiotensin II (AngII), a vasoactive peptide that elevates arterial blood pressure and results in hypertension, has been reported to directly induce vascular endothelial cell apoptosis. Recent work has demonstrated that propofol pre-treatment attenuates angiotensin II-induced apoptosis in human coronary artery endothelial cells. However, the underlying mechanism remains largely unknown. Here, we investigated human umbilical vein endothelial cells (HUVECs) subjected to angiotensin II-induced apoptosis in the presence or absence of propofol treatment and found that angiotensin II-induced apoptosis was attenuated by propofol in a dose-dependent manner. Furthermore, ELISA assays demonstrated that the ratio of angiotensin (1-7) (Ang (1-7)) to Ang II was increased after propofol treatment. We examined the expression of ACE2, Ang (1-7) and Mas and found that the ACE2-Ang (1-7)-Mas axis was up-regulated by propofol, while ACE2 overexpression increased phosphorylated endothelial nitric oxide synthase (phosphorylated eNOS) expression and siACE2 resulted in the repression of endothelial nitric oxide synthase (eNOS) phosphorylation. In conclusion, our study revealed that propofol can inhibit endothelial cell apoptosis induced by Ang II by activating the ACE2-Ang (1-7)-Mas axis and further up-regulating the expression and phosphorylation of eNOS.

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Project description:The angiopoietin-Tie signaling pathway is an important vascular signaling pathway involved in angiogenesis, vascular stability, and quiescence. Dysregulation in the pathway is linked to the impairments in vascular function associated with many diseases, including cancer, ocular diseases, systemic inflammation, and cardiovascular diseases. The present study uses a computational signaling pathway model validated against experimental data to quantitatively study various mechanistic aspects of the angiopoietin-Tie signaling pathway, including receptor activation, trafficking, turnover, and molecular mechanisms of its regulation. The model provides mechanistic insights into the controversial role of Ang2 and its regulators vascular endothelial protein tyrosine phosphatase (VE-PTP) and Tie1 and predicts synergistic effects of inhibition of VE-PTP, Tie1, and Tie2 cleavage on enhancing the vascular protective actions of Tie2.

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Endothelial cell-specific deficiency of Ang II type 1a receptors attenuates Ang II-induced ascending aortic aneurysms in LDL receptor-/- mice.

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Targeting the Angiopoietin-2/Tie-2 axis in conjunction with VEGF signal interference.

Project description:Anti-angiogenic therapies target the tumor vasculature, impairing its development and growth. It was hypothesized over 40 years ago by the late Judah Folkman and Julie Denekamp that depriving a tumor of oxygen and nutrients, by targeting the tumor vasculature, could have therapeutic benefits. Identification of growth factors and signaling pathways important in angiogenesis subsequently led to the development of a series of anti-angiogenic agents that over the past decade have become part of the standard of care in several disease settings. Unfortunately not all patients respond to the currently available anti-angiogenic therapies while others become resistant to these agents following prolonged exposure. Identification of new pathways that may drive angiogenesis led to the development of second-generation anti-angiogenic agents such as those targeting the Ang-2/Tie2 axis. Recently, it has become clear that combination of first and second generation agents targeting the blood vessel network can lead to outcomes superior to those using either agent alone. The present review focuses on the current status of VEGF and Ang-2 targeted agents and the potential utility of using them in combination to impair tumor angiogenesis.

| S-EPMC4394020 | biostudies-literature

Low Serum Angiopoietin-1, High Serum Angiopoietin-2, and High Ang-2/Ang-1 Protein Ratio are Associated with Early Onset Sepsis in Surinamese Newborns.

Project description:PURPOSE:Vascular inflammation and leakage in sepsis is mediated by Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) and their phosphorylation of the endothelial Tie-2 receptor. This study investigates levels of Ang-1 and Ang-2 in newborns to gain insight in the vascular pathophysiology of early onset sepsis (EOS) within 72?h after birth. METHODS:A prospective cohort study was performed among 71 Surinamese newborns treated with antibiotics for suspected EOS and 20 control newborns. Newborns with suspected EOS were divided in two groups: blood culture negative and positive EOS. Ang-1 and Ang-2 levels were measured in serum obtained at the start of antibiotic treatment and at re-evaluation after 48 to 72?h. RESULTS:In this cohort 8.5% of newborns had a positive blood culture. At the start of antibiotic treatment Ang-1 serum levels were lower (P?<?0.01), and Ang-2 and Ang-2/Ang-1 serum protein ratios were higher (P?<?0.01 and P?<?0.01, respectively) in newborns with blood culture positive EOS than in controls. These levels were not dependent on timing of first blood draw after birth. After 48 to 72?h levels of Ang-1 further decreased in blood culture positive EOS, while in the other groups no change was observed. CONCLUSIONS:Our findings support the hypothesis that a disbalance in the Angiopoietins plays a role in the vascular pathophysiology of EOS.

| S-EPMC5647105 | biostudies-literature

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