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Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Biopharmaceuticals".

Deadline for manuscript submissions: closed (23 December 2023) | Viewed by 29695

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Dr. Sylvain Broussy

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Faculty of Pharmacy, Université Paris Cité, Paris, France
Interests: medicinal chemistry; protein–protein interaction (PPI) inhibitors; organic synthesis and peptide synthesis; biochemical assays; molecular modeling

Special Issue Information

Dear Colleagues,

Vascular endothelial growth factors (VEGF-A/B/C/D and placental growth factor (PlGF)) and their receptors (VEGFRs) and co-receptor neuropilins (NRPs) are the main pro-angiogenic and lymphangiogenic factors in mammals. Pharmaceuticals targeting the VEGF/VEGFR axis have been successfully used to treat several cancers and ocular diseases but have shown some limitations, in particular regarding their long-term efficiency and their route of administration. In addition to small molecule inhibitors of the intracellular tyrosine kinase domain of the VEGFRs, inhibitors of extracellular VEGF/VEGFR protein–protein interaction have been developed. Among these ligands of VEGFs and of their receptors, compound classes were initially dominated by antibodies and aptamers. Interestingly, recent research has expanded to smaller molecular entities with designed properties such as nanobodies, peptides, and peptidomimetics. Moreover, new formulations and composition of matters are now developed to improve the delivery of inhibitors, specifically through ocular barriers. The conjugation of VEGF/VEGFR inhibitors with other molecular entities for specific targeting and for combination therapy is also a promising new strategy.

In this Special Issue, we aim to present significant research results in the field of VEGF/VEGFR inhibition that highlight the most recent strategies and promising therapeutic molecules. These studies will help to anticipate and shape the future therapeutic opportunities provided by an efficient modulation of this key axis in angiogenesis.

Dr. Sylvain Broussy
Guest Editor

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Keywords

vascular endothelial growth factors (VEGFs)
vascular endothelial growth factor receptors (VEGFRs)
placental growth factor (PlGF)
cytokines
inhibitors
protein–protein interaction inhibitors
small molecules
peptides
antibodies
aptamers
targeted delivery

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Published Papers (12 papers)

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Editorial

Jump to: Research, Review

3 pages, 186 KiB

Open AccessEditorial

Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease

by Sylvain Broussy

Pharmaceuticals 2024, 17(7), 959; https://doi.org/10.3390/ph17070959 - 18 Jul 2024

Viewed by 1308

Abstract

In this Special Issue of Pharmaceuticals, we present four reviews and seven original articles addressing recent aspects of research on Vascular Endothelial Growth Factors (VEGFs) and their receptors, from clinical practice to fundamental studies in new drug development [...] Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease)

Research

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12 pages, 1267 KiB

Open AccessArticle

Chirality and Rigidity in Triazole-Modified Peptidomimetics Interacting with Neuropilin-1

by Bartłomiej Fedorczyk, Patrycja Redkiewicz, Joanna Matalińska, Radosław Piast, Piotr Kosson and Rafał Wieczorek

Pharmaceuticals 2024, 17(2), 190; https://doi.org/10.3390/ph17020190 - 31 Jan 2024

Viewed by 1133

Abstract

The interaction of Neuropilin-1 (NRP-1) with vascular endothelial growth factor (VEGF) has been shown to promote angiogenesis under physiological and pathological conditions. Angiogenesis around tumors is a major factor allowing for their growth and spread. Disrupting NRP-1/VEGF complex formation is thus a promising pathway for the development of new anticancer pharmaceuticals. A large body of work has been produced in the last two decades detailing the development of inhibitors of NRP-1/VEGF complex formation. Among those were peptide A7R and its smaller derivatives KXXR and K(Har)XXR. It has been previously reported that replacement of the XX backbone with triazole residues has a positive effect on the proteolytic stability of inhibitors. It has also been reported that a higher dihedral angle range restriction of the XX backbone has a positive effect on the activity of inhibitors. In this work, we have designed new triazole derivatives of K(Har)XXR inhibitors with substitution allowing for higher range restriction of the XX backbone. The obtained peptidomimetics have greater activity than their less restricted counterparts. One of the newly obtained structures has greater affinity than the reference peptide A7R. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease)

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17 pages, 3327 KiB

Open AccessArticle

Relationships between Patient-Reported Outcome Measures and Clinical Measures in Naïve Neovascular Age-Related Macular Degeneration Patients Treated with Intravitreal Ranibizumab

by Pablo Almuiña-Varela, Laura García-Quintanilla, María José Rodríguez-Cid, María Gil-Martínez, Maximino J. Abraldes, Francisco Gómez-Ulla, Ana Estany-Gestal, Jorge Miguel Alcántara-Espinosa, Maribel Fernández-Rodríguez and Anxo Fernández-Ferreiro

Pharmaceuticals 2024, 17(2), 157; https://doi.org/10.3390/ph17020157 - 25 Jan 2024

Viewed by 1277

Abstract

Our objective was to evaluate changes in patient-reported outcome measures using the NEI-VFQ 25 questionnaire during a treat and extend regimen in naive neovascular Age-Related Macular Degeneration patients, and its correlation with anatomical and functional data. We conducted a prospective observational study. Patients underwent a treat and extend regimen with intravitreal ranibizumab for neovascular Age-Related Macular Degeneration. Initial response was evaluated at 4th month, and subsequently in every follow-up visit. If a clinical response was achieved, the injection interval was extended in two-week increments, up to a maximum of 12 weeks. Quality of life was assessed using the NEI-VFQ 25 questionnaire at baseline, 4th months, and 12th months. Patients were categorized as good or poor responders based on Best corrected visual acuity, central foveal thickness, intraretinal fluid, or subretinal fluid. Treatment with ranibizumab led to a significant improvement in quality of life, with a mean increase in NEI-VFQ 25 score of 4.27 points in the 12th month. No significant differences in improvement were observed between good and poor responders. Quality of life scores in neovascular Age-Related Macular Degeneration patients improved with intravitreal treatment regardless of the clinical response. The early response following the loading phase could indicate better quality of life after one year of treatment, with Best corrected visual acuity being the clinical parameter with the greatest influence on quality of life. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease)

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11 pages, 740 KiB

Open AccessArticle

Visual Outcomes of Anti-VEGF Treatment on Neovascular Age-Related Macular Degeneration: A Real-World Population-Based Cohort Study

by Ida Korva-Gurung, Anna-Maria Kubin, Pasi Ohtonen and Nina Hautala

Pharmaceuticals 2023, 16(7), 927; https://doi.org/10.3390/ph16070927 - 26 Jun 2023

Cited by 1 | Viewed by 2671

Abstract

Neovascular age-related macular degeneration (nAMD) leads to visual impairment if not treated promptly. Intravitreal anti-VEGF drugs have revolutionized nAMD treatment in the past two decades. We evaluated the visual outcomes of anti-VEGF treatment in nAMD. A real-life population-based cohort study. The data included parameters for age, sex, age at diagnosis, laterality, chronicity, symptoms, visual outcomes, lens status, and history of intravitreal injections. A total of 1088 eyes (827 patients) with nAMD were included. Visual acuity was stable or improved in 984 eyes (90%) after an average of 36 ± 25 months of follow-up. Bevacizumab was the first-line drug in 1083 (99.5%) eyes. Vision improved ≥15 ETDRS letters in 377 (35%), >5 ETDRS letters in 309 (28%), and was stable (±5 ETDRS letters) in 298 (27%) eyes after anti-VEGF treatment. The loss of 5 ≤ 15 ETDRS letters in 44 (4%) eyes and ≥15 ETDRS letters in 60 (6%) eyes was noted. At the diagnosis of nAMD, 110 out of 827 patients (13%) fulfilled the criteria for visual impairment, whereas 179 patients (22%) were visually impaired after the follow-up. Improvement or stabilization in vision was noted in 90% of the anti-VEGF-treated eyes with nAMD. In addition, anti-VEGF agents are crucial in diminishing nAMD-related visual impairment. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease)

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18 pages, 3473 KiB

Open AccessArticle

A VEGFB-Based Peptidomimetic Inhibits VEGFR2-Mediated PI3K/Akt/mTOR and PLCγ/ERK Signaling and Elicits Apoptotic, Antiangiogenic, and Antitumor Activities

by Mohadeseh Namjoo, Hossein Ghafouri, Elham Assareh, Amir Reza Aref, Ebrahim Mostafavi, Ali Hamrahi Mohsen, Saeed Balalaie, Sylvain Broussy and S. Mohsen Asghari

Pharmaceuticals 2023, 16(6), 906; https://doi.org/10.3390/ph16060906 - 20 Jun 2023

Cited by 7 | Viewed by 2394

Abstract

Vascular endothelial growth factor receptor 2 (VEGFR2) mediates VEGFA signaling mainly through the PI3K/AKT/mTOR and PLCγ/ERK1/2 pathways. Here we unveil a peptidomimetic (VGB3) based on the interaction between VEGFB and VEGFR1 that unexpectedly binds and neutralizes VEGFR2. Investigation of the cyclic and linear structures of VGB3 (named C-VGB3 and L-VGB3, respectively) using receptor binding and cell proliferation assays, molecular docking, and evaluation of antiangiogenic and antitumor activities in the 4T1 mouse mammary carcinoma tumor (MCT) model showed that loop formation is essential for peptide functionality. C-VGB3 inhibited proliferation and tubulogenesis of human umbilical vein endothelial cells (HUVECs), accounting for the abrogation of VEGFR2, p-VEGFR2 and, subsequently, PI3K/AKT/mTOR and PLCγ/ERK1/2 pathways. In 4T1 MCT cells, C-VGB3 inhibited cell proliferation, VEGFR2 expression and phosphorylation, the PI3K/AKT/mTOR pathway, FAK/Paxillin, and the epithelial-to-mesenchymal transition cascade. The apoptotic effects of C-VGB3 on HUVE and 4T1 MCT cells were inferred from annexin-PI and TUNEL staining and activation of P53, caspase-3, caspase-7, and PARP1, which mechanistically occurred through the intrinsic pathway mediated by Bcl2 family members, cytochrome c, Apaf-1 and caspase-9, and extrinsic pathway via death receptors and caspase-8. These data indicate that binding regions shared by VEGF family members may be important in developing novel pan-VEGFR inhibitors that are highly relevant in the pathogenesis of angiogenesis-related diseases. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease)

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17 pages, 2907 KiB

Open AccessArticle

Suramin Affects the Renal VEGF-A/VEGFR Axis in Short-Term Streptozotocin-Induced Diabetes

by Gabriela Chyła-Danił, Kornelia Sałaga-Zaleska, Ewelina Kreft, Aleksandra Krzesińska, Sylwia Herman, Agnieszka Kuchta, Monika Sakowicz-Burkiewicz, Małgorzata Lenartowicz and Maciej Jankowski

Pharmaceuticals 2023, 16(3), 470; https://doi.org/10.3390/ph16030470 - 22 Mar 2023

Cited by 1 | Viewed by 2699

Abstract

Diabetic nephropathy (DN) accounts for approximately 50% of end-stage renal diseases. Vascular endothelial growth factor A (VEGF-A) is thought to be a critical mediator of vascular dysfunction in DN, but its role is unclear. The lack of pharmacological tools to modify renal concentrations further hinders the understanding of its role in DN. In this study, rats were evaluated after 3 weeks of streptozotocin-induced diabetes and two suramin treatments (10 mg/kg, ip). Vascular endothelial growth factor A expression was evaluated by western blot of glomeruli and immunofluorescence of the renal cortex. RT-PCR for receptors Vegfr1 mRNA and Vegfr2 mRNA quantitation was performed. The soluble adhesive molecules (sICAM-1, sVCAM-1) in blood were measured by ELISA and the vasoreactivity of interlobar arteries to acetylcholine was evaluated using wire myography. Suramin administration reduced the expression and intraglomerular localisation of VEGF-A. Increased VEGFR-2 expression in diabetes was reduced by suramin to non-diabetic levels. Diabetes reduced the sVCAM-1 concentrations. Suramin in diabetes restored acetylcholine relaxation properties to non-diabetic levels. In conclusion, suramin affects the renal VEGF-A/VEGF receptors axis and has a beneficial impact on endothelium-dependent relaxation of renal arteries. Thus, suramin may be used as a pharmacological agent to investigate the potential role of VEGF-A in the pathogenesis of renal vascular complications in short-term diabetes. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease)

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14 pages, 9448 KiB

Open AccessArticle

Mechanism Underlying Triple VEGFR Inhibitor Tivozanib-Induced Hypertension in Mice Model

by Wael A. Alanazi, Abdulrahman S. Alanazi, Doaa M. El-Nagar, Abdullah M. Aljuraybah, Sary Alsanea and Metab Alharbi

Pharmaceuticals 2023, 16(2), 295; https://doi.org/10.3390/ph16020295 - 14 Feb 2023

Cited by 3 | Viewed by 2008

Abstract

Tivozanib is a triple vascular endothelial growth factor receptor inhibitor, recently approved for the treatment of refractory advanced renal cell carcinoma. Clinical studies showed that around 46% of patients who received tivozanib suffer from hypertension in all grades. Thus, the present study was conducted to identify the role of angiotensin-II (AngII) in the mechanism underlying tivozanib-induced vascular toxicity and hypertension. C57BL/6 male mice received tivozanib (1 mg/kg) with or without losartan (10 or 30 mg/kg) for 3 weeks. Blood pressure was recorded every 3 days, and proteinuria was measured every week. On day 21, all mice were euthanized, and samples were harvested for further analysis. Tivozanib elevated blood pressure until systolic blood pressure reached 163 ± 6.6 mmHg on day 21 of treatment with low urination and high proteinuria. AngII and its receptors, endothelin-1, and oxidative stress markers were significantly increased. While nitric oxide (NO) levels were reduced in plasma and aortic tissues. AngII type 1 receptor blockade by losartan prevented these consequences caused by tivozanib and kept blood pressure within normal range. The results showed that AngII and ET-1 might be potential targets in the clinical studies and management of hypertension induced by tivozanib. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease)

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15 pages, 3365 KiB

Open AccessArticle

Preclinical Studies of Chiauranib Show It Inhibits Transformed Follicular Lymphoma through the VEGFR2/ERK/STAT3 Signaling Pathway

by Yuanfang Tang, Mengya Zhong, Guangchao Pan, Jinshui Tan, Chendi Xie, Yuelong Jiang, Jingwei Yao, Weihang Shan, Jiaqi Lin, Jiewen Huang, Yating Liu, Zhifeng Li, Bing Xu and Jie Zha

Pharmaceuticals 2023, 16(1), 15; https://doi.org/10.3390/ph16010015 - 22 Dec 2022

Cited by 5 | Viewed by 2166

Abstract

Transformed follicular lymphoma (t-FL), for which there is no efficient treatment strategy, has a rapid progression, treatment resistance, and poor prognosis, which are the main reasons for FL treatment failure. In this study, we identified a promising therapeutic approach with chiauranib, a novel orally developed multitarget inhibitor targeting VEGFR/Aurora B/CSF-1R. We first determined the cytotoxicity of chiauranib in t-FL cell lines through CCK-8, EdU staining, flow cytometry, and transwell assays. We also determined the killing effect of chiauranib in a xenograft model. More importantly, we identified the underlying mechanism of chiauranib in t-FL tumorigenesis by immunofluorescence and Western blotting. Treatment with chiauranib significantly inhibited cell growth and migration, promoted apoptosis, induced cell cycle arrest in G2/M phase, and resulted in significant killing in vivo. Mechanistically, chiauranib suppresses the phosphorylation level of VEGFR2, which has an anti-t-FL effect by inhibiting the downstream MEK/ERK/STAT3 signaling cascade. In conclusion, chiauranib may be a potential therapy to treat t-FL, since it inhibits tumor growth and migration and induces apoptosis by altering the VEGFR2/ERK/STAT3 signaling pathway. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease)

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Review

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22 pages, 6890 KiB

Open AccessReview

Intravitreal Anti-Vascular Endothelial Growth Factor Therapies for Retinal Disorders

by Abraham Hang, Samuel Feldman, Aana P. Amin, Jorge A. Rivas Ochoa and Susanna S. Park

Pharmaceuticals 2023, 16(8), 1140; https://doi.org/10.3390/ph16081140 - 11 Aug 2023

Cited by 11 | Viewed by 3249

Abstract

Vascular endothelial growth factors (VEGFs) are key mediator of retinal and choroidal neovascularization as well as retinal vascular leakage leading to macular edema. As such, VEGF plays an important role in mediating visually significant complications associated with common retinal disorders such as diabetic retinopathy, retinal vein occlusion, and age-related macular degeneration. Various drugs that inhibit vascular endothelial growth factors (anti-VEGF therapies) have been developed to minimize vision loss associated with these disorders. These drugs are injected into the vitreous cavity in a clinic setting at regular intervals. This article provides an overview of the various anti-VEGF drugs used in ophthalmology and the common retinal conditions that benefit from this therapy. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease)

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19 pages, 11888 KiB

Open AccessReview

Structure-Based Design of Peptides Targeting VEGF/VEGFRs

by Rossella Di Stasi, Lucia De Rosa and Luca Domenico D’Andrea

Pharmaceuticals 2023, 16(6), 851; https://doi.org/10.3390/ph16060851 - 7 Jun 2023

Cited by 2 | Viewed by 2604

Abstract

Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) play a main role in the regulation of angiogenesis and lymphangiogenesis. Furthermore, they are implicated in the onset of several diseases such as rheumatoid arthritis, degenerative eye conditions, tumor growth, ulcers and ischemia. Therefore, molecules able to target the VEGF and its receptors are of great pharmaceutical interest. Several types of molecules have been reported so far. In this review, we focus on the structure-based design of peptides mimicking VEGF/VEGFR binding epitopes. The binding interface of the complex has been dissected and the different regions challenged for peptide design. All these trials furnished a better understanding of the molecular recognition process and provide us with a wealth of molecules that could be optimized to be exploited for pharmaceutical applications. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease)

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25 pages, 3114 KiB

Open AccessReview

Aptamers Versus Vascular Endothelial Growth Factor (VEGF): A New Battle against Ovarian Cancer

by Yachana Mishra, Aditi Chattaraj, Vijay Mishra, Abhigyan Ranjan and Murtaza M. Tambuwala

Pharmaceuticals 2023, 16(6), 849; https://doi.org/10.3390/ph16060849 - 6 Jun 2023

Cited by 4 | Viewed by 2200

Abstract

Cancer is one of the diseases that causes a high mortality as it involves unregulated and abnormal cell growth proliferation that can manifest in any body region. One of the typical ovarian cancer symptoms is damage to the female reproductive system. The death rate can be reduced through early detection of the ovarian cancer. Promising probes that can detect ovarian cancer are suitable aptamers. Aptamers, i.e., so-called chemical antibodies, have a strong affinity for the target biomarker and can typically be identified starting from a random library of oligonucleotides. Compared with other probes, ovarian cancer targeting using aptamers has demonstrated superior detection effectiveness. Various aptamers have been selected to detect the ovarian tumor biomarker, vascular endothelial growth factor (VEGF). The present review highlights the development of particular aptamers that target VEGF and detect ovarian cancer at its earliest stages. The therapeutic efficacy of aptamers in ovarian cancer treatment is also discussed. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease)

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23 pages, 1132 KiB

Open AccessEditor’s ChoiceReview

Recombinant Endostatin as a Potential Radiosensitizer in the Treatment of Non-Small Cell Lung Cancer

by Charnay Cunningham, Julie Bolcaen, Alessandra Bisio, Amanda Genis, Hans Strijdom and Charlot Vandevoorde

Pharmaceuticals 2023, 16(2), 219; https://doi.org/10.3390/ph16020219 - 31 Jan 2023

Cited by 4 | Viewed by 4423

Abstract

Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer, which is the leading cause of cancer-related deaths worldwide. Over the past decades, tumour angiogenesis has been intensely studied in the treatment of NSCLC due to its fundamental role in cancer progression. Several anti-angiogenic drugs, such as recombinant endostatin (RE), have been evaluated in several preclinical and clinical trials, with mixed and often disappointing results. However, there is currently an emerging interest in RE due to its ability to create a vascular normalization window, which could further improve treatment efficacy of the standard NSCLC treatment. This review provides an overview of preclinical and clinical studies that combined RE and radiotherapy for NSCLC treatment. Furthermore, it highlights the ongoing challenges that have to be overcome in order to maximize the benefit; as well as the potential advantage of combinations with particle therapy and immunotherapy, which are rapidly gaining momentum in the treatment landscape of NSCLC. Different angiogenic and immunosuppressive effects are observed between particle therapy and conventional X-ray radiotherapy. The combination of RE, particle therapy and immunotherapy presents a promising future therapeutic triad for NSCLC. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease)

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