Role of VEGFs in metabolic disorders

Somma, Margherita Di; Vliora, Maria; Grillo, Elisabetta; Castro, Bárbara Bruna Abreu de; Dakou, Eleni; Schaafsma, W.; Vanparijs, Jef; Corsini, Michela; Ravelli, Cosetta; Sakellariou, E.; Mitola, Stefania

doi:10.1007/s10456-019-09700-1

Cited by 37 publications

(22 citation statements)

References 126 publications

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“…CH is a pathophysiological response characterized by increased thickness of the ventricular wall, greater myocardial cell volume, and enhanced myocardial contractility in the early stage of overload pressure [1,3]. The pathophysiology of CH is complex and involves multiple cellular events, and the mechanisms of the development of CH are not fully understood [1,3,30]. Growing evidence indicates that mitochondrial dysfunction is closely related to the development and progression of CH.…”

Section: Discussionmentioning

confidence: 99%

Ndufs1 Deficiency Aggravates the Mitochondrial Membrane Potential Dysfunction in Pressure Overload-Induced Myocardial Hypertrophy

Zou

Tao

Qiu

et al. 2021

Oxidative Medicine and Cellular Longevity

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Mitochondrial dysfunction has been suggested to be the key factor in the development and progression of cardiac hypertrophy. The onset of mitochondrial dysfunction and the mechanisms underlying the development of cardiac hypertrophy (CH) are incompletely understood. The present study is based on the use of multiple bioinformatics analyses for the organization and analysis of scRNA-seq and microarray datasets from a transverse aortic constriction (TAC) model to examine the potential role of mitochondrial dysfunction in the pathophysiology of CH. The results showed that NADH:ubiquinone oxidoreductase core subunit S1- (Ndufs1-) dependent mitochondrial dysfunction plays a key role in pressure overload-induced CH. Furthermore, in vivo animal studies using a TAC mouse model of CH showed that Ndufs1 expression was significantly downregulated in hypertrophic heart tissue compared to that in normal controls. In an in vitro model of angiotensin II- (Ang II-) induced cardiomyocyte hypertrophy, Ang II treatment significantly downregulated the expression of Ndufs1 in cardiomyocytes. In vitro mechanistic studies showed that Ndufs1 knockdown induced CH; decreased the mitochondrial DNA content, mitochondrial membrane potential (MMP), and mitochondrial mass; and increased the production of mitochondrial reactive oxygen species (ROS) in cardiomyocytes. On the other hand, Ang II treatment upregulated the expression levels of atrial natriuretic peptide, brain natriuretic peptide, and myosin heavy chain beta; decreased the mitochondrial DNA content, MMP, and mitochondrial mass; and increased mitochondrial ROS production in cardiomyocytes. The Ang II-mediated effects were significantly attenuated by overexpression of Ndufs1 in rat cardiomyocytes. In conclusion, our results demonstrate downregulation of Ndufs1 in hypertrophic heart tissue, and the results of mechanistic studies suggest that Ndufs1 deficiency may cause mitochondrial dysfunction in cardiomyocytes, which may be associated with the development and progression of CH.

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Section: Discussionmentioning

confidence: 99%

Ndufs1 Deficiency Aggravates the Mitochondrial Membrane Potential Dysfunction in Pressure Overload-Induced Myocardial Hypertrophy

Zou

Tao

Qiu

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Oxidative Medicine and Cellular Longevity heterodimers with other transcription factors, leading to the upregulation of ER chaperone genes [90].…”

Section: Atf-6mentioning

confidence: 99%

Novel Insight into the Role of Endoplasmic Reticulum Stress in the Pathogenesis of Myocardial Ischemia-Reperfusion Injury

Zhu

Zhou

2021

Oxidative Medicine and Cellular Longevity

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Impaired function of the endoplasmic reticulum (ER) is followed by evolutionarily conserved cell stress responses, which are employed by cells, including cardiomyocytes, to maintain and/or restore ER homeostasis. ER stress activates the unfolded protein response (UPR) to degrade and remove abnormal proteins from the ER lumen. Although the UPR is an intracellular defense mechanism to sustain cardiomyocyte viability and heart function, excessive activation initiates ER-dependent cardiomyocyte apoptosis. Myocardial ischemia/reperfusion (I/R) injury is a pathological process occurring during or after revascularization of ischemic myocardium. Several molecular mechanisms contribute to the pathogenesis of cardiac I/R injury. Due to the dual protective/degradative effects of ER stress on cardiomyocyte viability and function, it is of interest to understand the basic concepts, regulatory signals, and molecular processes involved in ER stress following myocardial I/R injury. In this review, therefore, we present recent findings related to the novel components of ER stress activation. The complex effects of ER stress and whether they mitigate or exacerbate myocardial I/R injury are summarized to serve as the basis for research into potential therapies for cardioprotection through control of ER homeostasis.

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“…Indeed, multiple signaling pathways help coordinate these adipose tissue angiogenesis mechanisms, as detailed in several reviews (Cao, 2013;Escudero et al, 2017;Korybalska, 2018) despite the many angiogenic regulators, VEGF:VEGFR signaling is accepted as the primary adipose angiogenic pathway (Sung et al, 2013). In white adipose tissue, upregulation of VEGF-A:VEGFR2 signaling can promote tissue vascularization, increasing oxygen supply and subsequently enhancing energy consumption (di Somma et al, 2020). In addition, VEGF-A causes vascular fenestration, one of the structural bases that cause vascular permeability (Kamba et al, 2006).…”

Section: Vegf/vegfrs In Adipogenesis and Obesitymentioning

confidence: 99%

“…This model can be adapted to mechanistically explore the transcriptional pathways that connect VEGF:VEGFR signaling and adipocyte metabolism. For instance, this model can be used to reconstruct the VEGF-activated mitochondrial thermogenic activity and the browning of white adipocytes, and identify the key mitochondrial genes that regulate the VEGF expression in such processes ( di Somma et al, 2020 ). In addition, metabolites were separated by organelle (e.g., cytosol, mitochondria, extracellular space) to obtain a compartment-specific reconstruction.…”

Section: Systems Biology Provides a Platform For Investigating Vasculmentioning

confidence: 99%

Systems Biology Will Direct Vascular-Targeted Therapy for Obesity

2020

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Healthy adipose tissue expansion and metabolism during weight gain require coordinated angiogenesis and lymphangiogenesis. These vascular growth processes rely on the vascular endothelial growth factor (VEGF) family of ligands and receptors (VEGFRs). Several studies have shown that controlling vascular growth by regulating VEGF:VEGFR signaling can be beneficial for treating obesity; however, dysregulated angiogenesis and lymphangiogenesis are associated with several chronic tissue inflammation symptoms, including hypoxia, immune cell accumulation, and fibrosis, leading to obesity-related metabolic disorders. An ideal obesity treatment should minimize adipose tissue expansion and the advent of adverse metabolic consequences, which could be achieved by normalizing VEGF:VEGFR signaling. Toward this goal, a systematic investigation of the interdependency of vascular and metabolic systems in obesity and tools to predict personalized treatment ranges are necessary to improve patient outcomes through vascular-targeted therapies. Systems biology can identify the critical VEGF:VEGFR signaling mechanisms that can be targeted to regress adipose tissue expansion and can predict the metabolic consequences of different vasculartargeted approaches. Establishing a predictive, biologically faithful platform requires appropriate computational models and quantitative tissue-specific data. Here, we discuss the involvement of VEGF:VEGFR signaling in angiogenesis, lymphangiogenesis, adipogenesis, and macrophage specification-key mechanisms that regulate adipose tissue expansion and metabolism. We then provide useful computational approaches for simulating these mechanisms, and detail quantitative techniques for acquiring tissuespecific parameters. Systems biology, through computational models and quantitative data, will enable an accurate representation of obese adipose tissue that can be used to direct the development of vascular-targeted therapies for obesity and associated metabolic disorders.

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Role of VEGFs in metabolic disorders

Cited by 37 publications

References 126 publications

Ndufs1 Deficiency Aggravates the Mitochondrial Membrane Potential Dysfunction in Pressure Overload-Induced Myocardial Hypertrophy

Ndufs1 Deficiency Aggravates the Mitochondrial Membrane Potential Dysfunction in Pressure Overload-Induced Myocardial Hypertrophy

Novel Insight into the Role of Endoplasmic Reticulum Stress in the Pathogenesis of Myocardial Ischemia-Reperfusion Injury

Systems Biology Will Direct Vascular-Targeted Therapy for Obesity

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