Factors Determining Barrier Properties to Oxygen Transport Across Model and Cell Plasma Membranes Based on EPR Spin-Label Oximetry

Subczynski, Witold K.; Widomska, Justyna; Stein, Natalia; Swartz, Harold M.

doi:10.1007/s00723-021-01412-4

Cited by 6 publications

(6 citation statements)

References 116 publications

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“…Studies of in vitro artificial membranes and ex vivo natural membranes find increases in six membrane characteristics reduce trans membrane oxygen diffusion: unsaturation of membrane lipids, increased cytoskeletal elements, increased membrane stiffness, increased cholesterol, increased thickness, and increased protein content [78].…”

Section: Impedance To Transmembrane Oxygen Diffusionmentioning

confidence: 99%

“…At concentrations over about 50%, membrane saturation occurs which allows cholesterol/cholesterol bilayer domains to form. These domains have a PM about one tenth that of surrounding membranes and present a significant barrier to oxygen transport [82] . Dietary and environmental lipids are largely responsible for determining the cholesterol content and biophysical properties of endothelial and placental membranes.…”

Section: Impedance To Transmembrane Oxygen Diffusionmentioning

confidence: 99%

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Paradoxes: Cholesterol and Hypoxia in Preeclampsia

Hart

2024

Preprint

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Preeclampsia, a hypertensive disease of pregnancy of unknown etiology, is intensely studied as a model of cardiovascular (CVD) disease not only due to multiple shared pathologic elements, but also because changes that develop over decades in CVD disease appear and resolve within days in preeclampsia. Those affected by preeclampsia and their offspring experience increased lifetime risks of CVD. At the systemic level, preeclampsia is characterized by increased cellular, membrane, and blood levels of cholesterol, however, cholesterol dependent signaling such as canonical Wnt/βcatenin, Hedgehog, and endothelial nitric oxide synthase is downregulated indicating a cholesterol deficit with upregulation of cholesterol synthesis and efflux. Hypoxia related signaling in preeclampsia also appears paradoxical with increased Hypoxia Inducible Factors (HIF) in the placenta but measurably increased oxygen in maternal blood in placental villous spaces. This review addresses the molecular mechanisms by which excessive systemic cholesterol and deficient cholesterol dependent signaling may arise from the effects of dietary lipid variance causing the cellular hypoxia which characterizes preeclampsia.

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Section: Impedance To Transmembrane Oxygen Diffusionmentioning

confidence: 99%

Section: Impedance To Transmembrane Oxygen Diffusionmentioning

confidence: 99%

Paradoxes: Cholesterol and Hypoxia in Preeclampsia

Hart

2024

Preprint

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“…Studies of in vitro artificial membranes and ex vivo natural membranes show that a variety of changes in membranes reduce trans-membrane oxygen diffusion: unsaturation of membrane lipids, increased cytoskeletal elements, increased membrane stiffness, increased cholesterol, increased thickness, and increased protein content [ 79 ].…”

Section: Impedance To Transmembrane Oxygen Diffusionmentioning

confidence: 99%

Paradoxes: Cholesterol and Hypoxia in Preeclampsia

Hart

2024

Biomolecules

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Preeclampsia, a hypertensive disease of pregnancy of unknown etiology, is intensely studied as a model of cardiovascular disease (CVD) not only due to multiple shared pathologic elements but also because changes that develop over decades in CVD appear and resolve within days in preeclampsia. Those affected by preeclampsia and their offspring experience increased lifetime risks of CVD. At the systemic level, preeclampsia is characterized by increased cellular, membrane, and blood levels of cholesterol; however, cholesterol-dependent signaling, such as canonical Wnt/βcatenin, Hedgehog, and endothelial nitric oxide synthase, is downregulated indicating a cholesterol deficit with the upregulation of cholesterol synthesis and efflux. Hypoxia-related signaling in preeclampsia also appears to be paradoxical with increased Hypoxia-Inducible Factors in the placenta but measurably increased oxygen in maternal blood in placental villous spaces. This review addresses the molecular mechanisms by which excessive systemic cholesterol and deficient cholesterol-dependent signaling may arise from the effects of dietary lipid variance and environmental membrane modifiers causing the cellular hypoxia that characterizes preeclampsia.

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“…With the diffusion rate slowed at each transmembrane passage, cellular hypoxia may become clinically relevant. Thus, lipid variance may be the source of increased HIF signaling and sFlts seen in preeclampsia ( Subczynski et al, 2021 ).…”

Section: Inflammation Thrombosis and Oxidative Stress In Preeclampsia...mentioning

confidence: 99%

A theoretical model of dietary lipid variance as the origin of primary ciliary dysfunction in preeclampsia

Hart

2023

Front. Mol. Biosci.

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Serving as the cell’s key interface in communicating with the outside world, primary cilia have emerged as an area of multidisciplinary research interest over the last 2 decades. Although the term “ciliopathy” was first used to describe abnormal cilia caused by gene mutations, recent studies focus on abnormalities of cilia that are found in diseases without clear genetic antecedents, such as obesity, diabetes, cancer, and cardiovascular disease. Preeclampsia, a hypertensive disease of pregnancy, is intensely studied as a model for cardiovascular disease partially due to many shared pathophysiologic elements, but also because changes that develop over decades in cardiovascular disease arise in days with preeclampsia yet resolve rapidly after delivery, thus providing a time-lapse view of the development of cardiovascular pathology. As with genetic primary ciliopathies, preeclampsia affects multiple organ systems. While aspirin delays the onset of preeclampsia, there is no cure other than delivery. The primary etiology of preeclampsia is unknown; however, recent reviews emphasize the fundamental role of abnormal placentation. During normal embryonic development, trophoblastic cells, which arise from the outer layer of the 4-day-old blastocyst, invade the maternal endometrium and establish extensive placental vascular connections between mother and fetus. In primary cilia of trophoblasts, Hedgehog and Wnt/catenin signaling operate upstream of vascular endothelial growth factor to advance placental angiogenesis in a process that is promoted by accessible membrane cholesterol. In preeclampsia, impaired proangiogenic signaling combined with an increase in apoptotic signaling results in shallow invasion and inadequate placental function. Recent studies show primary cilia in preeclampsia to be fewer in number and shortened with functional signaling abnormalities. Presented here is a model that integrates preeclampsia lipidomics and physiology with the molecular mechanisms of liquid–liquid phase separation in model membrane studies and the known changes in human dietary lipids over the last century to explain how changes in dietary lipids might reduce accessible membrane cholesterol and give rise to shortened cilia and defects in angiogenic signaling, which underlie placental dysfunction of preeclampsia. This model offers a possible mechanism for non-genetic dysfunction in cilia and proposes a proof-of-concept study to treat preeclampsia with dietary lipids.

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Factors Determining Barrier Properties to Oxygen Transport Across Model and Cell Plasma Membranes Based on EPR Spin-Label Oximetry

Cited by 6 publications

References 116 publications

Paradoxes: Cholesterol and Hypoxia in Preeclampsia

Paradoxes: Cholesterol and Hypoxia in Preeclampsia

Paradoxes: Cholesterol and Hypoxia in Preeclampsia

A theoretical model of dietary lipid variance as the origin of primary ciliary dysfunction in preeclampsia

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