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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 March 2018) | Viewed by 99255

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Special Issue Editor

Prof. Kurt Ballmer-Hofer

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Guest Editor

1. Biomolecular Research, Paul Scherrer Institute, 5232-Villigen, Switzerland
2. Biocenter of the University of Basel, 4056-Basel, Switzerland
Interests: VEGF structure and function in angiogenesis; transmembrane signaling by receptor tyrosine kinases

Special Issue Information

Dear Colleagues,

A Special Issue on Vascular Endothelial Growth Factor, VEGF, is being prepared for the journal IJMS. VEGF was originally described as Vascular Permeability Factor, VPF, released by tumor tissue and later found to be the major driver of blood and lymphatic vessel development in mammals. VEGFs are derived from primordial molecules shaping the open vascular system of insects and comprise a family of four members. Additionally, functionally and structurally highly related homologues were found in pox viruses and snake venoms. The four VEGF genes in mammals give rise to a large number of functionally distinct protein isoforms that combinatorially activate three type V receptor tyrosine kinases. The dissection of the complexity of VEGF signaling is the focus of intense research and understanding VEGF signaling at the molecular level has great potential for future medical applications.

Altered functionality and expression of VEGFs and their receptors are the cause of severe human pathologies, such as retinopathies of the eye, atherosclerosis or the promotion and dissemination of cancer. Novel and more specific drugs must be developed for broad and successful application in the clinic in the future.

Prof. Kurt Ballmer-Hofer
Guest Editor

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Keywords

angiogenesis
receptor tyrosine kinase
signaling
vascular endothelial growth factor

Published Papers (12 papers)

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Editorial

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5 pages, 165 KiB

Open AccessEditorial

Vascular Endothelial Growth Factor, from Basic Research to Clinical Applications

by Kurt Ballmer-Hofer

Int. J. Mol. Sci. 2018, 19(12), 3750; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19123750 - 26 Nov 2018

Cited by 14 | Viewed by 2234

Abstract

Judah Folkman’s landmark discovery in the 1970s showing that tumors, growing beyond a few millimeters in diameter, depend on de novo vascularization triggered by specific growth factors released by tumor cells encountering hypoxia [...] Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor)

Research

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20 pages, 2431 KiB

Open AccessArticle

Oxygen-Induced Retinopathy from Recurrent Intermittent Hypoxia Is Not Dependent on Resolution with Room Air or Oxygen, in Neonatal Rats

by Kay D. Beharry, Charles L. Cai, Jacqueline Skelton, Faisal Siddiqui, Christina D’Agrosa, Johanna Calo, Gloria B. Valencia and Jacob V. Aranda

Int. J. Mol. Sci. 2018, 19(5), 1337; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19051337 - 01 May 2018

Cited by 12 | Viewed by 4071

Abstract

Preterm infants often experience intermittent hypoxia (IH) with resolution in room air (RA) or hyperoxia (Hx) between events. Hypoxia is a major inducer of vascular endothelial growth factor, which plays a key role in normal and aberrant retinal angiogenesis. This study tested the hypothesis that neonatal IH which resolved with RA is less injurious to the immature retina than IH resolved by Hx between events. Newborn rats were exposed to: (1) Hx (50% O₂) with brief hypoxia (12% O₂); (2) RA with 12% O₂; (3) Hx with RA; (4) Hx only; or (5) RA only, from P0 to P14. Pups were examined at P14 or placed in RA until P21. Retinal vascular and astrocyte integrity; retinal layer thickness; ocular and systemic biomarkers of angiogenesis; and somatic growth were determined at P14 and P21. All IH paradigms resulted in significant retinal vascular defects, disturbances in retinal astrocyte template, retinal thickening, and photoreceptor damage concurrent with elevations in angiogenesis biomarkers. These data suggest that the susceptibility of the immature retina to changes in oxygen render no differences in the outcomes between RA or O₂ resolution. Interventions and initiatives to curtail O₂ variations should remain a high priority to prevent severe retinopathy. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor)

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15 pages, 2714 KiB

Open AccessArticle

ScFvs as Allosteric Inhibitors of VEGFR-2: Novel Tools to Harness VEGF Signaling

by Kurt Ballmer-Hofer, Caroline A.C. Hyde, Thomas Schleier and Dragana Avramovic

Int. J. Mol. Sci. 2018, 19(5), 1334; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19051334 - 01 May 2018

Cited by 4 | Viewed by 4533

Abstract

Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) is the main mediator of angiogenic signaling in endothelial cells and a primary responder to VEGF. VEGF dependent VEGFR-2 activation regulates endothelial cell migration and proliferation, as well as vessel permeability. VEGF is presented as an antiparallel homodimer, and its binding to VEGFR-2 brings two receptors in close proximity. Downstream signaling is triggered by receptor dimerization, kinase activation, and receptor internalization. Our aim was to further investigate allosteric inhibition using binders targeting extracellular subdomains 4–7 of VEGFR-2 as an alternative to existing anti-angiogenic therapies, which rely on neutralizing VEGF or blocking of the ligand-binding site on the receptor. We applied phage display technology to produce single chain antibody fragments (scFvs) targeting VEGFR-2. Selected antibody fragments were characterized using biophysical and biological assays. We characterized several antibody fragments, which exert their inhibitory effect of VEGFR-2 independent of ligand binding. These reagents led to rapid clearance of VEGFR-2 from the cell surface without kinase activation, followed by an increase in intracellular receptor-positive vesicles, suggesting receptor internalization. Our highly specific VEGFR-2 binders thus represent novel tools for anti-angiogenic therapy and diagnostic applications. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor)

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Review

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14 pages, 2434 KiB

Open AccessReview

The Use of Vascular Endothelial Growth Factor Inhibitors and Complementary Treatment Options in Polypoidal Choroidal Vasculopathy: A Subtype of Neovascular Age-Related Macular Degeneration

by Kelvin Yi Chong Teo, Mark Gillies and Samantha Fraser-Bell

Int. J. Mol. Sci. 2018, 19(9), 2611; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19092611 - 03 Sep 2018

Cited by 23 | Viewed by 5129

Abstract

Polypoidal choroidal vasculopathy (PCV) is a subtype of neovascular age-related macular degeneration (AMD; nAMD) which occurs more commonly in Asian populations as compared to Caucasians. PCV and nAMD share pathological mechanisms, including pathological expression of vascular endothelial growth factor (VEGF). The advent of anti-vascular endothelial growth factor (VEGF) revolutionized the treatment of nAMD. Despite being a subtype of nAMD, PCV responds less well to VEGF inhibitors; thus, photodynamic therapy (PDT) in combination with anti-VEGF treatment may be considered. This review aims to summarize the current evidence for the treatment of PCV, especially whether VEGF inhibitors should be used alone or in combination with PDT. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor)

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18 pages, 470 KiB

Open AccessReview

VEGF Upregulation in Viral Infections and Its Possible Therapeutic Implications

by Khaled R. Alkharsah

Int. J. Mol. Sci. 2018, 19(6), 1642; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19061642 - 01 Jun 2018

Cited by 57 | Viewed by 7554

Abstract

Several viruses are recognized as the direct or indirect causative agents of human tumors and other severe human diseases. Vascular endothelial growth factor (VEGF) is identified as a principal proangiogenic factor that enhances the production of new blood vessels from existing vascular network. Therefore, oncogenic viruses such as Kaposi’s sarcoma herpesvirus (KSHV) and Epstein-Barr virus (EBV) and non-oncogenic viruses such as herpes simplex virus (HSV-1) and dengue virus, which lack their own angiogenic factors, rely on the recruitment of cellular genes for angiogenesis in tumor progression or disease pathogenesis. This review summarizes how human viruses exploit the cellular signaling machinery to upregulate the expression of VEGF and benefit from its physiological functions for their own pathogenesis. Understanding the interplay between viruses and VEGF upregulation will pave the way to design targeted and effective therapeutic approaches for viral oncogenesis and severe diseases. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor)

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12 pages, 1666 KiB

Open AccessReview

Polarised VEGFA Signalling at Vascular Blood–Neural Barriers

by Silvia Dragoni and Patric Turowski

Int. J. Mol. Sci. 2018, 19(5), 1378; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19051378 - 05 May 2018

Cited by 18 | Viewed by 6051

Abstract

At blood–neural barriers, endothelial VEGFA signalling is highly polarised, with entirely different responses being triggered by luminal or abluminal stimulation. These recent findings were made in a field which is still in its mechanistic infancy. For a long time, endothelial polarity has intuitively been presumed, and likened to that of epithelial cells, but rarely demonstrated. In the cerebral and the retinal microvasculature, the uneven distribution of VEGF receptors 1 and 2, with the former predominant on the luminal and the latter on the abluminal face of the endothelium, leads to a completely polarised signalling response to VEGFA. Luminal VEGFA activates VEGFR1 homodimers and AKT, leading to a cytoprotective response, whilst abluminal VEGFA induces vascular leakage via VEGFR2 homodimers and p38. Whilst these findings do not provide a complete picture of VEGFA signalling in the microvasculature—there are still unclear roles for heterodimeric receptor complexes as well as co-receptors—they provide essential insight into the adaptation of vascular systems to environmental cues that are naturally different, depending on whether they are present on the blood or tissue side. Importantly, sided responses are not only restricted to VEGFA, but exist for other important vasoactive agents. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor)

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20 pages, 1083 KiB

Open AccessReview

The Janus Face of VEGF in Stroke

by Samuel J. Geiseler and Cecilie Morland

Int. J. Mol. Sci. 2018, 19(5), 1362; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19051362 - 04 May 2018

Cited by 115 | Viewed by 7788

Abstract

The family of vascular endothelial growth factors (VEGFs) are known for their regulation of vascularization. In the brain, VEGFs are important regulators of angiogenesis, neuroprotection and neurogenesis. Dysregulation of VEGFs is involved in a large number of neurodegenerative diseases and acute neurological insults, including stroke. Stroke is the main cause of acquired disabilities, and normally results from an occlusion of a cerebral artery or a hemorrhage, both leading to focal ischemia. Neurons in the ischemic core rapidly undergo necrosis. Cells in the penumbra are exposed to ischemia, but may be rescued if adequate perfusion is restored in time. The neuroprotective and angiogenic effects of VEGFs would theoretically make VEGFs ideal candidates for drug therapy in stroke. However, contradictory to what one might expect, endogenously upregulated levels of VEGF as well as the administration of exogenous VEGF is detrimental in acute stroke. This is probably due to VEGF-mediated blood–brain-barrier breakdown and vascular leakage, leading to edema and increased intracranial pressure as well as neuroinflammation. The key to understanding this Janus face of VEGF function in stroke may lie in the timing; the harmful effect of VEGFs on vessel integrity is transient, as both VEGF preconditioning and increased VEGF after the acute phase has a neuroprotective effect. The present review discusses the multifaceted action of VEGFs in stroke prevention and therapy. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor)

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16 pages, 15018 KiB

Open AccessReview

Positive and Negative Regulation of Angiogenesis by Soluble Vascular Endothelial Growth Factor Receptor-1

by Cristina M. Failla, Miriam Carbo and Veronica Morea

Int. J. Mol. Sci. 2018, 19(5), 1306; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19051306 - 27 Apr 2018

Cited by 56 | Viewed by 7764

Abstract

Vascular endothelial growth factor receptor (VEGFR)-1 exists in different forms, derived from alternative splicing of the same gene. In addition to the transmembrane form, endothelial cells produce a soluble VEGFR-1 (sVEGFR-1) isoform, whereas non-endothelial cells produce both sVEGFR-1 and a different soluble molecule, known as soluble fms-like tyrosine kinase (sFlt)1-14. By binding members of the vascular endothelial growth factor (VEGF) family, the soluble forms reduce the amounts of VEGFs available for the interaction with their transmembrane receptors, thereby negatively regulating VEGFR-mediated signaling. In agreement with this activity, high levels of circulating sVEGFR-1 or sFlt1-14 are associated with different pathological conditions involving vascular dysfunction. Moreover, sVEGFR-1 and sFlt1-14 have an additional role in angiogenesis: they are deposited in the endothelial cell and pericyte extracellular matrix, and interact with cell membrane components. Interaction of sVEGFR-1 with α5β1 integrin on endothelial cell membranes regulates vessel growth, triggering a dynamic, pro-angiogenic phenotype. Interaction of sVEGFR-1/sFlt1-14 with cell membrane glycosphingolipids in lipid rafts controls kidney cell morphology and glomerular barrier functions. These cell–matrix contacts represent attractive novel targets for pharmacological intervention in addition to those addressing interactions between VEGFs and their receptors. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor)

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17 pages, 975 KiB

Open AccessReview

VEGF (Vascular Endothelial Growth Factor) and Fibrotic Lung Disease

by Shaney L. Barratt, Victoria A. Flower, John D. Pauling and Ann B. Millar

Int. J. Mol. Sci. 2018, 19(5), 1269; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19051269 - 24 Apr 2018

Cited by 75 | Viewed by 8293

Abstract

Interstitial lung disease (ILD) encompasses a group of heterogeneous diseases characterised by varying degrees of aberrant inflammation and fibrosis of the lung parenchyma. This may occur in isolation, such as in idiopathic pulmonary fibrosis (IPF) or as part of a wider disease process affecting multiple organs, such as in systemic sclerosis. Anti-Vascular Endothelial Growth Factor (anti-VEGF) therapy is one component of an existing broad-spectrum therapeutic option in IPF (nintedanib) and may become part of the emerging therapeutic strategy for other ILDs in the future. This article describes our current understanding of VEGF biology in normal lung homeostasis and how changes in its bioavailability may contribute the pathogenesis of ILD. The complexity of VEGF biology is particularly highlighted with an emphasis on the potential non-vascular, non-angiogenic roles for VEGF in the lung, in both health and disease. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor)

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27 pages, 3196 KiB

Open AccessReview

Molecular Pharmacology of VEGF-A Isoforms: Binding and Signalling at VEGFR2

by Chloe J. Peach, Viviane W. Mignone, Maria Augusta Arruda, Diana C. Alcobia, Stephen J. Hill, Laura E. Kilpatrick and Jeanette Woolard

Int. J. Mol. Sci. 2018, 19(4), 1264; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19041264 - 23 Apr 2018

Cited by 279 | Viewed by 27414

Abstract

Vascular endothelial growth factor-A (VEGF-A) is a key mediator of angiogenesis, signalling via the class IV tyrosine kinase receptor family of VEGF Receptors (VEGFRs). Although VEGF-A ligands bind to both VEGFR1 and VEGFR2, they primarily signal via VEGFR2 leading to endothelial cell proliferation, survival, migration and vascular permeability. Distinct VEGF-A isoforms result from alternative splicing of the Vegfa gene at exon 8, resulting in VEGF_xxxa or VEGF_xxxb isoforms. Alternative splicing events at exons 5–7, in addition to recently identified posttranslational read-through events, produce VEGF-A isoforms that differ in their bioavailability and interaction with the co-receptor Neuropilin-1. This review explores the molecular pharmacology of VEGF-A isoforms at VEGFR2 in respect to ligand binding and downstream signalling. To understand how VEGF-A isoforms have distinct signalling despite similar affinities for VEGFR2, this review re-evaluates the typical classification of these isoforms relative to the prototypical, “pro-angiogenic” VEGF₁₆₅a. We also examine the molecular mechanisms underpinning the regulation of VEGF-A isoform signalling and the importance of interactions with other membrane and extracellular matrix proteins. As approved therapeutics targeting the VEGF-A/VEGFR signalling axis largely lack long-term efficacy, understanding these isoform-specific mechanisms could aid future drug discovery efforts targeting VEGF receptor pharmacology. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor)

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15 pages, 4124 KiB

Open AccessReview

Vascular Endothelial Growth Factor-A Exerts Diverse Cellular Effects via Small G Proteins, Rho and Rap

by Akio Shimizu, Dimitar P. Zankov, Misuzu Kurokawa-Seo and Hisakazu Ogita

Int. J. Mol. Sci. 2018, 19(4), 1203; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19041203 - 16 Apr 2018

Cited by 23 | Viewed by 6159

Abstract

Vascular endothelial growth factors (VEGFs) include five molecules (VEGF-A, -B, -C, -D, and placental growth factor), and have various roles that crucially regulate cellular functions in many kinds of cells and tissues. Intracellular signal transduction induced by VEGFs has been extensively studied and is usually initiated by their binding to two classes of transmembrane receptors: receptor tyrosine kinase VEGF receptors (VEGF receptor-1, -2 and -3) and neuropilins (NRP1 and NRP2). In addition to many established results reported by other research groups, we have previously identified small G proteins, especially Ras homologue gene (Rho) and Ras-related protein (Rap), as important mediators of VEGF-A-stimulated signaling in cancer cells as well as endothelial cells. This review article describes the VEGF-A-induced signaling pathways underlying diverse cellular functions, including cell proliferation, migration, and angiogenesis, and the involvement of Rho, Rap, and their related molecules in these pathways. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor)

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22 pages, 1441 KiB

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VEGF Signaling in Neurological Disorders

by Joon W. Shim and Joseph R. Madsen

Int. J. Mol. Sci. 2018, 19(1), 275; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19010275 - 17 Jan 2018

Cited by 101 | Viewed by 11203

Abstract

Vascular endothelial growth factor (VEGF) is a potent growth factor playing diverse roles in vasculogenesis and angiogenesis. In the brain, VEGF mediates angiogenesis, neural migration and neuroprotection. As a permeability factor, excessive VEGF disrupts intracellular barriers, increases leakage of the choroid plexus endothelia, evokes edema, and activates the inflammatory pathway. Recently, we discovered that a heparin binding epidermal growth factor like growth factor (HB-EGF)—a class of EGF receptor (EGFR) family ligands—contributes to the development of hydrocephalus with subarachnoid hemorrhage through activation of VEGF signaling. The objective of this review is to entail a recent update on causes of death due to neurological disorders involving cerebrovascular and age-related neurological conditions and to understand the mechanism by which angiogenesis-dependent pathological events can be treated with VEGF antagonisms. The Global Burden of Disease study indicates that cancer and cardiovascular disease including ischemic and hemorrhagic stroke are two leading causes of death worldwide. The literature suggests that VEGF signaling in ischemic brains highlights the importance of concentration, timing, and alternate route of modulating VEGF signaling pathway. Molecular targets distinguishing two distinct pathways of VEGF signaling may provide novel therapies for the treatment of neurological disorders and for maintaining lower mortality due to these conditions. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor)

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