Adenoviral VEGF-B186R127S gene transfer induces angiogenesis and improves perfusion in ischemic heart

Korpela, H; Hätinen, Olli-Pekka; Nieminen, Tiina; Mallick, Rahul; Toivanen, Pekka; Airaksinen, J.; Valli, Kaisa; Hakulinen, Mikko; Poutiainen, Pekka; Nurro, Jussi; Ylä‐Herttuala, Seppo

doi:10.1016/j.isci.2021.103533

Cited by 6 publications

(14 citation statements)

References 31 publications

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“…To avoid this problem, we recently designed different isoforms of VEGF-B186, as it was unclear whether the angiogenic potential or arrhythmogenic stimuli of VEGF-B186 is due to the full-length VEGF-B186 or whether NRP1 binding after the proteolytic processing contributes to these effects. We demonstrated that full-length VEGF-B186 is solely responsible for angiogenesis, and no arrhythmogenic stimuli were observed with the full length or the NRP1 binding isoforms in this study ( Korpela et al, 2021 ).…”

Section: Introductionmentioning

confidence: 57%

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Novel Designed Proteolytically Resistant VEGF-B186R127S Promotes Angiogenesis in Mouse Heart by Recruiting Endothelial Progenitor Cells

Mallick

Gurzeler²,

Toivanen³

et al. 2022

Front. Bioeng. Biotechnol.

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Background: Previous studies have indicated that vascular endothelial growth factor B186 (VEGF-B186) supports coronary vascular growth in normal and ischemic myocardium. However, previous studies also indicated that induction of ventricular arrhythmias is a severe side effect preventing the use of VEGF-B186 in cardiac gene therapy, possibly mediated by binding to neuropilin 1 (NRP1). We have designed a novel VEGF-B186 variant, VEGF-B186R127S, which is resistant to proteolytic processing and unable to bind to NRP1. Here, we studied its effects on mouse heart to explore the mechanism of VEGF-B186-induced vascular growth along with its effects on cardiac performance.Methods: Following the characterization of VEGF-B186R127S, we performed ultrasound-guided adenoviral VEGF-B186R127S gene transfers into the murine heart. Vascular growth and heart functions were analyzed using immunohistochemistry, RT-PCR, electrocardiogram and ultrasound examinations. Endothelial progenitor cells (EPCs) were isolated from the circulating blood and characterized. Also, in vitro experiments were carried out in cardiac endothelial cells with adenoviral vectors.Results: The proteolytically resistant VEGF-B186R127S significantly induced vascular growth in mouse heart. Interestingly, VEGF-B186R127S gene transfer increased the number of circulating EPCs that secreted VEGF-A. Other proangiogenic factors were also present in plasma and heart tissue after the VEGF-B186R127S gene transfer. Importantly, VEGF-B186R127S gene transfer did not cause any side effects, such as arrhythmias.Conclusion: VEGF-B186R127S induces vascular growth in mouse heart by recruiting EPCs. VEGF-B186R127S is a novel therapeutic agent for cardiac therapeutic angiogenesis to rescue myocardial tissue after an ischemic insult.

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Section: Introductionmentioning

confidence: 57%

“…Human serotype 5 adenoviral vectors were produced by National Virus Vector Laboratory at Biocenter Kuopio, Finland ( Korpela et al, 2021 ). Adenoviral vector titers were spectrophotometrically determined at OD260 nm ( Sweeney and Hennessey, 2002 ).…”

Section: Methodsmentioning

confidence: 99%

Novel Designed Proteolytically Resistant VEGF-B186R127S Promotes Angiogenesis in Mouse Heart by Recruiting Endothelial Progenitor Cells

Mallick

Gurzeler²,

Toivanen³

et al. 2022

Front. Bioeng. Biotechnol.

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“…VEGF-B mainly binds to VEGFR-1 and NRP-1, and plays an important role in tumor angiogenesis and in the improvement of ischemic conditions [29,30]. VEGF-C and VEGF-D mainly bind to VEGFR-3 and participate in lymphangiogenesis [30,31].…”

Section: Angiogenic Function: Tumor Vasculaturementioning

confidence: 99%

VEGF/VEGFR-Targeted Therapy and Immunotherapy in Non-small Cell Lung Cancer: Targeting the Tumor Microenvironment

Zhao¹,

Guo²,

Deng³

et al. 2022

Int. J. Biol. Sci.

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Non-small cell lung cancer (NSCLC) is the leading cause of death by cancer worldwide. Despite developments in therapeutic approaches for the past few decades, the 5-year survival rate of patients with NSCLC remains low. NSCLC tumor is a complex, heterogeneous microenvironment, comprising blood vessels, cancer cells, immune cells, and stroma cells. Vascular endothelial growth factors (VEGFs) are a major mediator to induce tumor microvasculature and are associated with the progression, recurrence, and metastasis of NSCLC. Current treatment medicines targeting VEGF/VEGF receptor (VEGFR) pathway, including neutralizing antibodies to VEGF or VEGFR and receptor tyrosine kinase inhibitors, have shown good treatment efficacy in patients with NSCLC. VEGF is not only an important angiogenic factor but also an immunomodulator of tumor microenvironment (TME). VEGFs can suppress antigen presentation, stimulate activity of regulatory T (Treg) cells, and tumor-associated macrophages, which in turn promote an immune suppressive microenvironment in NSCLC. The present review focuses on the angiogenic and non-angiogenic functions of VEGF in NSCLC, especially the interaction between VEGF and the cellular components of the TME. Additionally, we discuss recent preclinical and clinical studies to explore VEGF/VEGFR-targeted compounds and immunotherapy as novel approaches targeting the TME for the treatment of NSCLC.

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“…In connection with coronary vessels, VEGF-B promotes angiogenesis in the subendocardial region and rescues the myocardium after myocardial infarction [ 52 ]. Our studies have shown that adenoviral vector-based VEGF-B186 gene transfer induced significant angiogenesis in the myocardium and improved myocardial perfusion without increasing a coronary steal effect [ 28 , 43 , 45 , 55 ]. Thus, VEGF-B186 seems highly beneficial for the treatment of CHD [ 43 , 45 ].…”

Section: Cardioprotective Role Of Vegf-bmentioning

confidence: 99%

“…Our studies have shown that adenoviral vector-based VEGF-B186 gene transfer induced significant angiogenesis in the myocardium and improved myocardial perfusion without increasing a coronary steal effect [ 28 , 43 , 45 , 55 ]. Thus, VEGF-B186 seems highly beneficial for the treatment of CHD [ 43 , 45 ]. However, it has remained unclear if both unprocessed and proteolytically processed forms or specific forms of VEGF-B186 contribute to the neovascularization process.…”

Section: Cardioprotective Role Of Vegf-bmentioning

confidence: 99%

Therapeutic Potential of VEGF-B in Coronary Heart Disease and Heart Failure: Dream or Vision?

Mallick

Ylä‐Herttuala

2022

Cells

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Coronary heart disease (CHD) is the leading cause of death around the world. Based on the roles of vascular endothelial growth factor (VEGF) family members to regulate blood and lymphatic vessels and metabolic functions, several therapeutic approaches have been attempted during the last decade. However proangiogenic therapies based on classical VEGF-A have been disappointing. Therefore, it has become important to focus on other VEGFs such as VEGF-B, which is a novel member of the VEGF family. Recent studies have shown the very promising potential of the VEGF-B to treat CHD and heart failure. The aim of this review article is to present the role of VEGF-B in endothelial biology and as a potential therapeutic agent for CHD and heart failure. In addition, key differences between the VEGF-A and VEGF-B effects on endothelial functions are demonstrated.

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Adenoviral VEGF-B186R127S gene transfer induces angiogenesis and improves perfusion in ischemic heart

Cited by 6 publications

References 31 publications

Novel Designed Proteolytically Resistant VEGF-B186R127S Promotes Angiogenesis in Mouse Heart by Recruiting Endothelial Progenitor Cells

Novel Designed Proteolytically Resistant VEGF-B186R127S Promotes Angiogenesis in Mouse Heart by Recruiting Endothelial Progenitor Cells

VEGF/VEGFR-Targeted Therapy and Immunotherapy in Non-small Cell Lung Cancer: Targeting the Tumor Microenvironment

Therapeutic Potential of VEGF-B in Coronary Heart Disease and Heart Failure: Dream or Vision?

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