VEGFR-1/Flt-1 inhibition increases angiogenesis and improves muscle function in a mouse model of Duchenne muscular dystrophy

Bosco, Jennifer; Zhou, Zhiwei; Gabriëls, Sofie; Verma, Mayank; Liu, Nan; Miller, Brian K.; Gu, Shuang‐Xi; Lundberg, Dianna; Huang, Yan; Brown, Eilish; Josiah, Serene; Meiyappan, Muthuraman; Traylor, Matthew J.; Chen, Nancy; Asakura, Atsushi; Jonge, Natalie De; Blanchetot, Christophe; Haard, Hans de; Keefe, Dennis

doi:10.1016/j.omtm.2021.03.013

Cited by 12 publications

(13 citation statements)

References 58 publications

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“…VEGFA and FLT1 targeted therapies are being explored as both pro-and anti-angiogenic therapies for several indications including retinal degeneration, cancer, pre-eclampsia and neuromuscular diseases (Bae et al, 2005;Keifer et al, 2014;Mac Gabhann et al, 2011;Verma et al, 2010;Verma et al, 2019;Bosco et al, 2021;Xin et al, 2021). As these therapies mature, it will be important to ascertain the MuSC-specific effects of VEGFA and FLT1.…”

Section: Discussionmentioning

confidence: 99%

Endothelial cell signature in muscle stem cells validated by VEGFA-FLT1-AKT1 axis promoting survival of muscle stem cell

Verma

Asakura

Wang

et al. 2021

Preprint

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Endothelial and skeletal muscle lineages arise from common embryonic progenitors. Despite their shared developmental origin, adult endothelial cells (ECs) and muscle stem cells (MuSCs) (satellite cells) have been thought to possess distinct gene signatures and signaling pathways. Here we shift this paradigm by uncovering how adult MuSC behavior is affected by the expression of a subset of EC transcripts. We used several computational analyses including single-cell RNAseq to show that MuSCs express low levels of canonical EC markers. We demonstrate that MuSC survival is regulated by one such prototypic endothelial signaling pathway (VEGFA-FLT1). Using pharmacological and genetic gain- and loss-of-function studies, we identify the FLT1-AKT1 axis as the key effector underlying VEGFA-mediated regulation of MuSC survival. All together, our data support that the VEGFA-FLT1-AKT1 pathway promotes MuSC survival during muscle regeneration, and highlights how the minor expression of select transcripts is sufficient for affecting cell behavior.

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Section: Discussionmentioning

confidence: 99%

Endothelial cell signature in muscle stem cells validated by VEGFA-FLT1-AKT1 axis promoting survival of muscle stem cell

Verma

Asakura

Wang

et al. 2021

Preprint

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“…Similarly, Clément d’Audigier et al reported that VEGFR1 inhibition of endothelial progenitors downregulates their differentiation potential in vivo and in vitro [ 40 ]. In addition, some studies indicated that endothelial cell-specific VEGFR1 deletion increased the coronary vasculature and induced cardiomyocyte hypertrophy in healthy adult mice [ 41 ] and also increased vascular density, increased satellite cell numbers, and improved functions in Duchenne muscular dystrophy mice [ 42 , 43 ]. Additionally, these authors explained that endothelial VEGFR1 deletion improved heart growth and repairment via VEGFR2-mediated angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of VEGFB/VEGFR1 Signaling Promotes White Adipose Tissue Browning and Skeletal Muscle Development

Ling

Lai

Quan

et al. 2022

IJMS

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It has been demonstrated that vascular endothelial growth factor B (VEGFB) and vascular endothelial growth factor receptor 1 (VEGFR1) play a vital role in regulating vascular biological function. However, the role of VEGFB and VEGFR1 in regulating fat deposition and skeletal muscle growth remains unclear. Therefore, this study was conducted to investigate the effects of VEGFB and VEGFR1 on fat deposition and skeletal muscle growth in mice. Our results showed that knockdown of VEGFB decreased body weight and iWAT index, stimulated the browning of mice iWAT with increased expression of UCP1, decreased the diameters of adipocytes, and elevated energy expenditure. In contrast, knockdown of VEGFB increased gastrocnemius (GAS) muscle index with increased proliferation of GAS muscle by expression of PCNA and Cyclin D1. Meanwhile, knockdown of endothelial VEGFR1 induced the browning of iWAT with increased expression of UCP1 and decreased diameters of adipocytes. By contrast, knockdown of endothelial VEGFR1 inhibited GAS muscle differentiation with decreased expression of MyoD. In conclusion, these results suggested that the loss of VEGFB/VEGFR1 signaling is associated with enhanced browning of inguinal white adipose tissue and skeletal muscle development. These results provided new insights into the regulation of skeletal muscle growth and regeneration, as well as fat deposition, suggesting the potential application of VEGFB/VEGFR1 as an intervention for the restriction of muscle diseases and obesity and related metabolic disorders.

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“…In the present study, decreased capillary density was seen with the decreased KDR expression in the soleus muscle of HFpEF mice. KDR is predominantly expressed in the vascular endothelial cells and mediates signaling to promote angiogenesis ( 63 , 64 ). The decreased KDR expression in HFpEF mice was accompanied by a significant increase in VEGF-α expression, which may be a compensatory response to receptor downregulation.…”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle phenotypic switching in heart failure with preserved ejection fraction

Saw

Werner

Zamani

et al. 2022

Front. Cardiovasc. Med.

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BackgroundSkeletal muscle (SkM) phenotypic switching is associated with exercise intolerance in heart failure with preserved ejection fraction (HFpEF). Patients with HFpEF have decreased type-1 oxidative fibers and mitochondrial dysfunction, indicative of impaired oxidative capacity. The SAUNA (SAlty drinking water/Unilateral Nephrectomy/Aldosterone) mice are commonly used in HFpEF pre-clinical studies and demonstrate cardiac, lung, kidney, and white adipose tissue impairments. However, the SkM (specifically the oxidative-predominant, soleus muscle) has not been described in this preclinical HFpEF model. We sought to characterize the soleus skeletal muscle in the HFpEF SAUNA mice and investigate its translational potential.MethodsHFpEF was induced in mice by uninephrectomy, d-aldosterone or saline (Sham) infusion by osmotic pump implantation, and 1% NaCl drinking water was given for 4 weeks. Mice were euthanized, and the oxidative-predominant soleus muscle was collected. We examined fiber composition, fiber cross-sectional area, capillary density, and fibrosis. Molecular analyses were also performed. To investigate the clinical relevance of this model, the oxidative-predominant, vastus lateralis muscle from patients with HFpEF was biopsied and examined for molecular changes in mitochondrial oxidative phosphorylation, vasculature, fibrosis, and inflammation.ResultsHistological analyses demonstrated a reduction in the abundance of oxidative fibers, type-2A fiber atrophy, decreased capillary density, and increased fibrotic area in the soleus muscle of HFpEF mice compared to Sham. Expression of targets of interest such as a reduction in mitochondrial oxidative-phosphorylation genes, increased VEGF-α and an elevated inflammatory response was also seen. The histological and molecular changes in HFpEF mice are consistent and comparable with changes seen in the oxidative-predominant SkM of patients with HFpEF.ConclusionThe HFpEF SAUNA model recapitulates the SkM phenotypic switching seen in HFpEF patients. This model is suitable and relevant to study SkM phenotypic switching in HFpEF.

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VEGFR-1/Flt-1 inhibition increases angiogenesis and improves muscle function in a mouse model of Duchenne muscular dystrophy

Cited by 12 publications

References 58 publications

Endothelial cell signature in muscle stem cells validated by VEGFA-FLT1-AKT1 axis promoting survival of muscle stem cell

Endothelial cell signature in muscle stem cells validated by VEGFA-FLT1-AKT1 axis promoting survival of muscle stem cell

Knockdown of VEGFB/VEGFR1 Signaling Promotes White Adipose Tissue Browning and Skeletal Muscle Development

Skeletal muscle phenotypic switching in heart failure with preserved ejection fraction

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