Excess Circulating Angiopoietin-2 May Contribute to Pulmonary Vascular Leak in Sepsis in Humans

Parikh, Samir M.; Mammoto, Tadanori; Schultz, Aylit; Yuan, Hai-Tao; Christiani, David C.; Karumanchi, S. Ananth; Sukhatme, Vikas P.

doi:10.1371/journal.pmed.0030046

Cited by 454 publications

(524 citation statements)

References 58 publications

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“…In fact, angiopoietin 2 release has been shown to be responsible for the sepsis-induced leakage of pulmonary blood vessels. 25 It was also suggested that angiopoietin 2 participates in the recruitment of bone marrow-derived endothelial precursors, as well as stimulates EPC migration. 26,27 It is quite possible that the observed recruitment of stem cells in our studies represents another facet of the same phenomenon-the stress-induced response.…”

Section: Discussionmentioning

confidence: 99%

Ischemia-Induced Exocytosis of Weibel-Palade Bodies Mobilizes Stem Cells

Kuo

Patschan

et al. 2008

Journal of the American Society of Nephrology

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Recruitment of various stem and progenitor cells is crucial for the regeneration of an injured organ. Levels of uric acid, one of the prototypical "alarm signals," surge after ischemia-reperfusion injury. Exogenous uric acid rapidly mobilizes endothelial progenitor cells and hematopoietic stem cells and protects the kidney from ischemia. The relatively fast responses to uric acid suggest that preformed second messengers may be released from a storage pool. Here, it is reported that monosodium urate (MSU) results in exocytosis of Weibel-Palade bodies in vitro and in vivo, leading to the release of IL-8, von Willebrand factor, and angiopoietin 2 in the culture medium or circulation. Confocal and immunoelectron microscopy confirmed depletion of von Willebrand factor in MSU-treated aortic endothelial cells. Angiopoietin 2 alone induced exocytosis of Weibel-Palade bodies, mobilized hematopoietic stem cells and depleted splenic endothelial progenitor cells, partially reproducing the actions of MSU. In addition, pretreatment with angiopoietin 2 protected the kidneys from an ischemic insult, suggesting that the previously reported renoprotection conferred by MSU likely results from exocytosis of Weibel-Palade bodies. Furthermore, experiments with toll-like receptor 4 (TLR-4)-and TLR-2-deficient mice demonstrated that uric acid-induced exocytosis of Weibel-Palade bodies is mediated by TLR-4 and that uric acid-induced release of IL-8 requires both TLR-2 and TLR-4. In summary, these results suggest that exocytosis of Weibel-Palade bodies links postischemic repair with inflammation and mobilization of stem cells.

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Section: Discussionmentioning

confidence: 99%

Ischemia-Induced Exocytosis of Weibel-Palade Bodies Mobilizes Stem Cells

Kuo

Patschan

et al. 2008

Journal of the American Society of Nephrology

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“…55,56 Since sepsis is characterized by vascular leakage, Ang2 has also been implicated in this condition in humans. 57,58 …”

Section: Angiopoietinmentioning

confidence: 99%

The Role of Angiopoietin 2 in Hyperoxia-Inuduced Acute Lung Injury

Bhandari¹,

Elias²

2007

Cell Cycle

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“…A systemic increase in permeability, leading to a degree of vascular leak that impairs organ function, is a hallmark of sepsis, a lethal syndrome of multiorgan dysfunction that arises as a result of disseminated infection. We have previously shown that Tie-2 inhibition induces changes in the endothelial cytoskeleton that are mediated by the small GTPase RhoA and lead to increased cell contraction and enhanced vascular permeability (7). These experiments suggest that the anti-permeability effect of activated Tie-2 may depend on endothelial cytoskeletal forces and cell architecture.…”

mentioning

confidence: 92%

Angiopoietin-1 Requires p190 RhoGAP to Protect against Vascular Leakage in Vivo

Mammoto¹,

Parikh²,

Mammoto

et al. 2007

Journal of Biological Chemistry

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159

219

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Angiopoietin-1 (Ang-1), a ligand of the endothelium-specific receptor Tie-2, inhibits permeability in the mature vasculature, but the mechanism remains unknown. Here we show that Ang-1 signals Rho family GTPases to organize the cytoskeleton into a junction-fortifying arrangement that enhances the permeability barrier function of the endothelium. Ang-1 phosphorylates Tie-2 and its downstream effector phosphatidylinositol 3-kinase. This induces activation of one endogenous GTPase, Rac1, and inhibition of another, RhoA. Loss of either part of this dual effect abrogates the cytoskeletal and anti-permeability actions of Ang-1, suggesting that coordinated GTPase regulation is necessary for the vessel-sealing effects of Ang-1. p190 RhoGAP, a GTPase regulatory protein, provides this coordinating function as it is phosphorylated by Ang-1 treatment, requires Rac1 activation, and is necessary for RhoA inhibition. Ang-1 prevents the cytoskeletal and pro-permeability effects of endotoxin but requires p190 RhoGAP to do so. Treatment with p190 RhoGAP small interfering RNA completely abolishes the ability of Ang-1 to rescue endotoxemia-induced pulmonary vascular leak and inflammation in mice. We conclude that Ang-1 prevents vascular permeability by regulating the endothelial cytoskeleton through coordinated and opposite effects on the Rho GTPases Rac1 and RhoA. By linking Rac1 activation and RhoA inhibition, p190 RhoGAP is critical to the protective effects of Ang-1 against endotoxin. These results provide mechanistic evidence that targeting the endothelium through Tie-2 may offer specific therapeutic strategies in life-threatening endotoxemic conditions such as sepsis and acute respiratory distress syndrome. Angiopoietin-1 (Ang-1)3 is a 498-amino acid secreted glycoprotein whose germ line depletion leads to several cardiovascular defects that result in embryonic lethality (1, 2). Although made by numerous cell types, the actions of Ang-1 are primarily mediated by a receptor tyrosine kinase, Tie-2, whose expression is largely restricted to endothelial cells (ECs). Critical roles for Ang-1 and Tie-2 have been described in the formation of the primitive cardiac tube and embryonic vasculature (3). Although necessary for developmental angiogenesis to occur, Ang-1 expression and Tie-2 phosphorylation persist into adulthood in organs not considered angiogenically active (4), suggesting a nonangiogenic role in the mature vasculature. In fact, Ang-1 has been shown to protect adult blood vessels against plasma leakage because of vascular endothelial growth factor or mustard oil (5, 6). However, the mechanism by which Ang-1 defends against vascular leakage in vivo has remained largely unknown.Permeability is a tightly regulated feature of all vascular beds. A systemic increase in permeability, leading to a degree of vascular leak that impairs organ function, is a hallmark of sepsis, a lethal syndrome of multiorgan dysfunction that arises as a result of disseminated infection. We have previously shown that Tie-2 inhibition induces changes...

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Excess Circulating Angiopoietin-2 May Contribute to Pulmonary Vascular Leak in Sepsis in Humans

Cited by 454 publications

References 58 publications

Ischemia-Induced Exocytosis of Weibel-Palade Bodies Mobilizes Stem Cells

Ischemia-Induced Exocytosis of Weibel-Palade Bodies Mobilizes Stem Cells

The Role of Angiopoietin 2 in Hyperoxia-Inuduced Acute Lung Injury

Angiopoietin-1 Requires p190 RhoGAP to Protect against Vascular Leakage in Vivo

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