Loss of Akt activity increases circulating soluble endoglin release in preeclampsia: Identification of inter-dependency between Akt-1 and heme oxygenase-1

University / BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
European Heart Journal (Impact Factor: 15.2). 03/2011; 33(9):1150-8. DOI: 10.1093/eurheartj/ehr065
Source: PubMed

ABSTRACT Endothelial dysfunction is a hallmark of preeclampsia. Desensitization of the phosphoinositide 3-kinase (PI3K)/Akt pathway underlies endothelial dysfunction and haeme oxygenase-1 (HO-1) is decreased in preeclampsia. To identify therapeutic targets, we sought to assess whether these two regulators act to suppress soluble endoglin (sEng), an antagonist of transforming growth factor-β (TGF-β) signalling, which is known to be elevated in preeclampsia.
Vascular endothelial growth factor-A (VEGF-A), fibroblast growth factor (FGF-2), angiopoietin-1 (Ang-1), and insulin, which all activate the PI3K/Akt pathway, inhibited the release of sEng from endothelial cells. Inhibition of the PI3K/Akt pathway, by overexpression of phosphatase and tensin homolog (PTEN) or a dominant-negative isoform of Akt (Akt(dn)) induced sEng release from endothelial cells and prevented the inhibitory effect of VEGF-A. Conversely, overexpression of a constitutively active Akt (Akt(myr)) inhibited PTEN and cytokine-induced sEng release. Systemic delivery of Akt(myr) to mice significantly reduced circulating sEng, whereas Akt(dn) promoted sEng release. Phosphorylation of Akt was reduced in preeclamptic placenta and this correlated with the elevated level of circulating sEng. Knock-down of Akt using siRNA prevented HO-1-mediated inhibition of sEng release and reduced HO-1 expression. Furthermore, HO-1 null mice have reduced phosphorylated Akt in their organs and overexpression of Akt(myr) failed to suppress the elevated levels of sEng detected in HO-1 null mice, indicating that HO-1 is required for the Akt-mediated inhibition of sEng.
The loss of PI3K/Akt and/or HO-1 activity promotes sEng release and positive manipulation of these pathways offers a strategy to circumvent endothelial dysfunction.

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Available from: Takeshi Fujisawa, Sep 28, 2015
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    • "Please cite this article in press as: H.E.J. Yong, et al., Anti-angiogenic collagen fragment arresten is increased from 16 weeks' gestation in preeclamptic plasma, Placenta (2015), endothelial permeability and decreased endothelial tube formation [47] [48]. Fas ligand is also significantly increased in the circulation of PE women [49]. "
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    ABSTRACT: Introduction: Arresten and canstatin are endogenous anti-angiogenic factors derived from type IV collagen α-chains COL4A1 and COL4A2 respectively. While their functions are explored in cancer studies, little is known about their role in pregnancy. Pre-eclampsia (PE) is a common, serious hypertensive disorder of pregnancy that is characterised by systemic endothelial dysfunction. COL4A1 and COL4A2 are maternal PE susceptibility genes that have increased mRNA expression in PE decidua. Our study aim was to determine the levels of arresten and canstatin in plasma and decidua from PE and gestational age matched normotensive patients. Methods: Plasma was collected from normotensive (n = 44) and PE (n = 39) women during the second and third trimesters of pregnancy. Third trimester decidua was collected at delivery from normotensive and PE women (n = 4 each). Levels of arresten and canstatin were determined by Western immunoblotting. Results: Arresten levels were significantly increased in second and third trimester PE plasma, and in third trimester PE decidua (p < 0.05). Third trimester PE plasma arresten levels also significantly correlated with the need for MgSO4 treatment, where a 1.7 fold increase was observed in patients requiring MgSO4 treatment (p < 0.05). No significant change in canstatin levels was observed between normotensive and PE patients. Discussion: This is the first study to report significant increases in the levels of collagen fragment arresten in PE plasma and decidua. Given its significant increase before the onset of clinical disease and associations with clinical severity in the third trimester, arresten may be a useful biomarker for predicting PE and monitoring its severity.
    Placenta 09/2015; DOI:10.1016/j.placenta.2015.08.013 · 2.71 Impact Factor
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    • "The PI3K/Akt pathway is one of the major downstream targets of the insulin pathway and is negatively regulated by phosphatase and tensin homologue deleted on chromosome 10 (PTEN) [34]. The activation of the PI3K/Akt pathway inhibits the release of soluble Eng from endothelial cells [35]. Conversely, the inhibition of the PI3K/Akt pathway, by overexpression of PTEN stimulates soluble Eng release from endothelial cells [35]. "
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    ABSTRACT: Endoglin is a transmembrane auxiliary receptor for transforming growth factor-beta (TGF-beta) that is predominantly expressed on proliferating endothelial cells. It plays a wide range of physiological roles but its importance on energy balance or insulin sensitivity has been unexplored. Endoglin deficient mice die during midgestation due to cardiovascular defects. Here we report for first time that heterozygous endoglin deficiency in mice decreases high fat diet-induced hepatic triglyceride content and insulin levels. Importantly, these effects are independent of changes in body weight or adiposity. At molecular level, we failed to detect relevant changes in the insulin signalling pathway at basal levels in liver, muscle or adipose tissues that could explain the insulin-dependent effect. However, we found decreased triglyceride content in the liver of endoglin heterozygous mice fed a high fat diet in comparison to their wild type littermates. Overall, our findings indicate that endoglin is a potentially important physiological mediator of insulin levels and hepatic lipid metabolism.
    PLoS ONE 03/2013; 8(1):e54591. DOI:10.1371/journal.pone.0054591 · 3.23 Impact Factor
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    • "However, our study supports a previously proposed idea that endoglin has cellular effects independent of TGFβ [9], [49], [65], [66]. There are only a few works in the literature that relates endoglin and PI3K-Akt pathway and almost all of them refer a regulation of endoglin expression by PI3K-Akt pathway [67], [68], [69], [70], [71]. According with our results, very recently, Lee et al. shown the PI3K/Akt pathway as an endoglin target in regulating the stabilization of capillary sprouts and endothelial cell survival. "
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    ABSTRACT: Accurate regulation of dermal fibroblast function plays a crucial role in wound healing. Many fibrotic diseases are characterized by a failure to conclude normal tissue repair and the persistence of fibroblasts inside lesions. In the present study we demonstrate that endoglin haploinsufficiency promotes fibroblast accumulation during wound healing. Moreover, scars from endoglin-heterozygous (Eng(+/-)) mice show persisting fibroblasts 12 days after wounding, which could lead to a fibrotic scar. Endoglin haploinsufficiency results in increased proliferation and migration of primary cultured murine dermal fibroblasts (MDFs). Moreover, Eng(+/-) MDF have diminished responses to apoptotic signals compared with control cells. Altogether, these modifications could explain the augmented presence of fibroblasts in Eng(+/-) mice wounds. We demonstrate that endoglin expression regulates Akt phosphorylation and that PI3K inhibition abolishes the differences in proliferation between endoglin haploinsufficient and control cells. Finally, persistent fibroblasts in Eng(+/-) mice wound co-localize with a greater degree of Akt phosphorylation. Thus, endoglin haploinsufficiency seems to promote fibroblast accumulation during wound healing through the activation of the PI3K/Akt pathway. These studies open new non-Smad signaling pathway for endoglin regulating fibroblast cell function during wound healing, as new therapeutic opportunities for the treatment of fibrotic wounds.
    PLoS ONE 01/2013; 8(1):e54687. DOI:10.1371/journal.pone.0054687 · 3.23 Impact Factor
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