Impaired autophagy by soluble endoglin, under physiological hypoxia in early pregnant period, is involved in poor placentation in preeclampsia

Nakashima, Akitoshi; Yamanaka-Tatematsu, Mikiko; Fujita, Naonobu; Koizumi, Keiichi; Saito, Tomoko; Yoshida, Toshiko; Nikaido, Toshio; Okamoto, Aikou; Yoshimori, Tamotsu; Saito, Shigeru

doi:10.4161/auto.22927

Cited by 180 publications

(201 citation statements)

References 49 publications

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“…During a normal pregnancy, extravillous trophoblasts invade the uterine spiral arteries and replace pre-existing vascular endothelial cells. This process appears to require autophagy-competent trophoblasts 49 . Moreover, soluble ENG /endoglin (that functions as a co-receptor for TGFB /TGF-β signaling) appears to inhibit trophoblast invasion, at least in part by suppressing autophagy.…”

Section: Autophagy Extracellular Matrix and Angiogenesismentioning

confidence: 99%

The Role of Autophagy in Vascular Biology

Nussenzweig

Verma

Finkel

2015

Circulation Research

215

150

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There is increasing interest in the role of autophagic flux in maintaining normal vessel wall biology, as well as a growing suspicion that autophagic dysregulation may be a common pathway through which vascular aging and associated pathologies develop. Within endothelial and smooth muscle cells, diverse but important triggers that range from oxidized lipids to β-amyloid appear to potently stimulate autophagosome formation. In addition, emerging evidence links autophagy to a wide array of vascular processes ranging from angiogenesis to calcification of the vessel wall. Alterations in autophagic flux are also increasingly being implicated in disease processes that include both atherosclerosis and pulmonary hypertension. Finally, recent insights point towards an important role of autophagy in the paracrine regulation of vasoactive substances from the endothelium. Here, we review the progress in understanding how autophagy can contribute to vascular biology and the emerging strategies to target this process for therapeutic benefit.

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Section: Autophagy Extracellular Matrix and Angiogenesismentioning

confidence: 99%

The Role of Autophagy in Vascular Biology

Nussenzweig

Verma

Finkel

2015

Circulation Research

215

150

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“…Nakashima et al 42 found autophagy deficient cells showed reduced trophoblast invasion capacity under hypoxic conditions.…”

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confidence: 99%

Autophagy regulation of physiological and pathological processes in the female reproductive tract

Cao

Camden

Parnell

et al. 2017

American J Rep Immunol

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Autophagy is a ubiquitous cell recycling pathway that delivers cytoplasmic constituents to the lysosome and is essential for normal cellular function. Autophagic activity is up‐regulated under physiological conditions as well as stressful conditions such as nutrient deprivation, oxidative stress, hypoxia, inflammation, and infection. Thus, it is essential to regard the functional importance of the pathway and its components in a given tissue context. Here we review what is known about the involvement of autophagy process during physiological processes in the female reproductive tract and in pregnancy from preimplantation to oocyte function to placental development, parturition, and postpartum remodeling of the uterus; as well as in pathological and adverse events during these processes.

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“…Culture-based experiments have confirmed that oxygen deficiency induces autophagy in primary human trophoblast cells ). In addition, hypoxia-induced autophagy has been shown to enhance the invasion capacity of EVT (Nakashima et al 2013). However, it has also been reported that inhibition of production of autophagy-related proteins by siRNA transfection had no effect on invasion activity of a trophoblast cell line (Hung et al 2013).…”

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confidence: 99%

The influence of oxidative stress and autophagy cross regulation on pregnancy outcome

Ramos

2016

Cell Stress and Chaperones

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The generation of reactive oxygen species (ROS), a byproduct of aerobic energy metabolism, is maintained at physiological levels by the activity of antioxidant components. Insufficiently opposed ROS results in oxidative stress characterized by altered mitochondrial function, decreased protein activity, damage to nucleic acids, and induction of apoptosis. Elevated levels of inadequately opposed ROS induce autophagy, a major intracellular pathway that sequesters and removes damaged macromolecules and organelles. In early pregnancy, autophagy induction preserves trophoblast function in the low oxygen and nutrient placental environment. Inadequate regulation of the ROS-autophagy axis leads to abnormal autophagy activity and contributes to the development of preeclampsia and intrauterine growth restriction. ROS-autophagy interactions are altered at the end of gestation and participate in the initiation of parturition at term. The induction of high levels of ROS coupled with a failure to induce a corresponding increase in autophagy results in the triggering of preterm labor and delivery.Keywords Oxidative stress . Autophagy . Preeclampsia . Intrauterine growth restriction . Preterm birth . PregnancyReactive oxygen species (ROS), such as superoxide radicals, hydroxyl radicals, alkoxy radicals as well as the non-radical intermediates hydrogen peroxide, ozone, and singlet oxygen, are byproducts of aerobic energy metabolism (Sies 1991;Finkel 2011). The concentration of these radicals is maintained at physiological levels by activity of the antioxidant enzymes superoxide dismutase, catalase, and peroxiredoxins as well as by concentrations of glutathione and vitamins C and E. When this system becomes out of balance, the generation of insufficiently opposed ROS results in altered mitochondrial function, a diminution of protein activity, damage to nucleic acids, and induction of apoptosis. The consequent tissue damage is manifested in a range of pathologies to different organ systems (Domingueti et al. 2015;Aluganti et al. 2016;Hernández et al. 2016). Recently, insufficiently regulated ROS has been recognized as a major contributor to disorders of pregnancy (Coppe et al. 2010;Redman and Sargent 2010;Menon 2014; Wu et al. 2015a, b;Zhang et al. 2015).A major pathway for removing macromolecules and organelles that have been damaged by ROS is macroautophagy, hereafter referred to as autophagy. This catabolic process is responsible for eliminating altered proteins, mitochondria, and inflammasomes from the cytoplasm. Macromolecules and organelles marked for destruction are enclosed within a doublemembrane structure called autophagosome. Its subsequent fusion with a lysosome results in degradation of the enclosed entity and release of the component amino acids, carbohydrates, nucleic acid degradation products, and lipids into the cytoplasm as building blocks for synthesis of new macromolecules or for the generation of energy by mitochondria. Autophagy is a constitutive process and functions at a low level under physiologica...

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Impaired autophagy by soluble endoglin, under physiological hypoxia in early pregnant period, is involved in poor placentation in preeclampsia

Cited by 180 publications

References 49 publications

The Role of Autophagy in Vascular Biology

The Role of Autophagy in Vascular Biology

Autophagy regulation of physiological and pathological processes in the female reproductive tract

The influence of oxidative stress and autophagy cross regulation on pregnancy outcome

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