Endothelial-specific FoxO1 depletion prevents obesity-related disorders by increasing vascular metabolism and growth

Rudnicki, Martina; Abdifarkosh, Ghoncheh; Nwadozi, Emmanuel; Ramos, Sofhia V.; Makki, Armin; Sepa-Kishi, Diane M.; Ceddia, Rolando B.; Roudier, Emilie; Haas, Tara L.

doi:10.7554/elife.39780

Cited by 44 publications

(37 citation statements)

References 45 publications

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“…Forkhead box O transcription factor 1 (FOXO1) was recently shown to link the proliferative and metabolic pathways in ECs and its EC-specific deletion led to uncoordinated growth of vessels via elevated glycolysis and mitochondrial respiration, thereby contributing to the plasticity of ECs to respond to external stimuli [ 112 ]. In line with this, an EC-specific deletion of Foxo1 in mice improved the proliferative capacity of ECs and prevented HFD-induced capillary rarefaction in AT [ 113 ].…”

Section: Factors Regulating Capillary Density In Obesitymentioning

confidence: 90%

Capillary Rarefaction in Obesity and Metabolic Diseases—Organ-Specificity and Possible Mechanisms

Paavonsalo

Hariharan

Lackman

et al. 2020

Cells

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Obesity and its comorbidities like diabetes, hypertension and other cardiovascular disorders are the leading causes of death and disability worldwide. Metabolic diseases cause vascular dysfunction and loss of capillaries termed capillary rarefaction. Interestingly, obesity seems to affect capillary beds in an organ-specific manner, causing morphological and functional changes in some tissues but not in others. Accordingly, treatment strategies targeting capillary rarefaction result in distinct outcomes depending on the organ. In recent years, organ-specific vasculature and endothelial heterogeneity have been in the spotlight in the field of vascular biology since specialized vascular systems have been shown to contribute to organ function by secreting varying autocrine and paracrine factors and by providing niches for stem cells. This review summarizes the recent literature covering studies on organ-specific capillary rarefaction observed in obesity and metabolic diseases and explores the underlying mechanisms, with multiple modes of action proposed. It also provides a glimpse of the reported therapeutic perspectives targeting capillary rarefaction. Further studies should address the reasons for such organ-specificity of capillary rarefaction, investigate strategies for its prevention and reversibility and examine potential signaling pathways that can be exploited to target it.

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Section: Factors Regulating Capillary Density In Obesitymentioning

confidence: 90%

Capillary Rarefaction in Obesity and Metabolic Diseases—Organ-Specificity and Possible Mechanisms

Paavonsalo

Hariharan

Lackman

et al. 2020

Cells

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“…There is further evidence of direct crosstalk between ECs and adipocytes/AT. The endothelial-specific knockdown of the transcription factor Forkhead Box O1 (FoxO1) led to a higher vascular density in AT ( Rudnicki et al, 2018 ). Under the high-fat diet, VAT displays a higher expression of Pecam1, higher capillary number per adipocyte, reduced triglycerides in blood and less hepatic lipid accumulation.…”

Section: Metabolic Disorders Related To Obesity and Cardiovascular Comentioning

confidence: 99%

Angiogenesis in Adipose Tissue: The Interplay Between Adipose and Endothelial Cells

Herold

Kalucka

2021

Front. Physiol.

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Obesity is a worldwide health problem, and as its prevalence increases, so does the burden of obesity-associated co-morbidities like type 2 diabetes or cardiovascular diseases (CVDs). Adipose tissue (AT) is an endocrine organ embedded in a dense vascular network. AT regulates the production of hormones, angiogenic factors, and cytokines. During the development of obesity, AT expands through the increase in fat cell size (hypertrophy) and/or fat cell number (hyperplasia). The plasticity and expansion of AT is related to its angiogenic capacities. Angiogenesis is a tightly orchestrated process, which involves endothelial cell (EC) proliferation, migration, invasion, and new tube formation. The expansion of AT is accelerated by hypoxia, inflammation, and structural remodeling of blood vessels. The paracrine signaling regulates the functional link between ECs and adipocytes. Adipocytes can secrete both pro-angiogenic molecules, e.g., tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), or vascular endothelial growth factor (VEGF), and anti-angiogenic factors, e.g., serpins. If the pro-angiogenic molecules dominate, the angiogenesis is dysregulated and the endothelium becomes dysfunctional. However, if anti-angiogenic molecules are overexpressed relative to the angiogenic regulators, the angiogenesis is repressed, and AT becomes hypoxic. Furthermore, in the presence of chronic nutritional excess, endothelium loses its primary function and contributes to the inflammation and fibrosis of AT, which increases the risk for CVDs. This review discusses the current understanding of ECs function in AT, the cross-talk between adipose and ECs, and how obesity can lead to its dysfunction. Understanding the interplay of angiogenesis with AT can be an approach to therapy obesity and obesity-related diseases such as CVDs.

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“…Furthermore, in response to hypoxia, VEGF increases PFKFB3 expression to enhance glycolysis in ECs. However, high glucose reduces PFKFB3 expression in the mouse ECs [ 48 ]. These studies suggest that hyperglycemia downregulates two critical promoters of angiogenesis: HIF-1α and PFKFB3 in ECs.…”

Section: Ec Glucose Metabolism In Pathological Angiogenesismentioning

confidence: 99%

Endothelial Cell Glucose Metabolism and Angiogenesis

Ren

Hamblin

et al. 2021

Biomedicines

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Angiogenesis, a process of new blood vessel formation from the pre-existing vascular bed, is a critical event in various physiological and pathological settings. Over the last few years, the role of endothelial cell (EC) metabolism in angiogenesis has received considerable attention. Accumulating studies suggest that ECs rely on aerobic glycolysis, rather than the oxidative phosphorylation pathway, to produce ATP during angiogenesis. To date, numerous critical regulators of glucose metabolism, fatty acid oxidation, and glutamine metabolism have been identified to modulate the EC angiogenic switch and pathological angiogenesis. The unique glycolytic feature of ECs is critical for cell proliferation, migration, and responses to environmental changes. In this review, we provide an overview of recent EC glucose metabolism studies, particularly glycolysis, in quiescent and angiogenic ECs. We also summarize and discuss potential therapeutic strategies that take advantage of EC metabolism. The elucidation of metabolic regulation and the precise underlying mechanisms could facilitate drug development targeting EC metabolism to treat angiogenesis-related diseases.

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Endothelial-specific FoxO1 depletion prevents obesity-related disorders by increasing vascular metabolism and growth

Cited by 44 publications

References 45 publications

Capillary Rarefaction in Obesity and Metabolic Diseases—Organ-Specificity and Possible Mechanisms

Capillary Rarefaction in Obesity and Metabolic Diseases—Organ-Specificity and Possible Mechanisms

Angiogenesis in Adipose Tissue: The Interplay Between Adipose and Endothelial Cells

Endothelial Cell Glucose Metabolism and Angiogenesis

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