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Angiogenesis in Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 40902

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Dr. Diego La Mendola

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Guest Editor

Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
Interests: bioinorganic chemistry; coordination chemistry; neurochemistry; angiogenesis; metal ions; peptides
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Maria Letizia Trincavelli

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Co-Guest Editor

Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
Interests: cell signaling; signal transduction; cell proliferation; apoptosis; cell line culture; primary cell culture; immunoprecipitation; cancer biology
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Prof. Dr. Claudia Martini

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Co-Guest Editor

Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
Interests: neurochemistry; neurodegeneration; signaling: receptors interactions; receptor metabolism; life/death/differentiation signaling; traslocator protein
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Angiogenesis is the physiological process by which new blood capillaries form from the existing vasculature.

Excessive angiogenesis has been implicated, directly or indirectly, in many disorders and among them cancer, autoimmune diseases, diabetic retinopathy, rheumatoid arthritis and atherosclerosis. Conversely, insufficient vascularization and inadequate blood vessels growth can underpin or contribute to cerebral ischemia, coronary heart disease and delayed wound healing.

Angiogenesis is a dynamic and complex process regulated by a very sensitive interplay of different growth factor and inhibitors; the maintenance of their correct balance is essential for physiological control of blood vessel growth.

The interaction between neoplastic cells and newly formed vessels is one of the fundamental biological events involved in the growth of solid tumor growth and metastases formation. The so-called “angiogenic switch” is an alteration in the balance of pro-angiogenic and anti-angiogenic molecules, with an increase of activators, that can be determined by a local change in tissue environment, as hypoxia, low pH, injury, inflammation and metal ions dyshomeostasis.

Angiogenesis is also a prominent features of brain aging and neurological diseases, either as pathophysiological factor or as a response to injury. Most cases of Alzheimer’s disease have variable degrees of concomitant vascular pathology, including atherosclerosis, microvascular degeneration, blood-brain barrier dysfunction and cerebral amyloid angiopathy. The increased leakiness in the blood vessels disrupts the blood‐brain barrier and allows unwanted blood products to enter the brain causing progression of disease pathology and promoting amyloid aggregation. Increased numbers of endothelial cell nuclei and blood vessels have been found postmortem in the substantia nigra of patients affected by Parkinson’s disease.

The interaction between cell growth factors as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), angiopoietin, platelet derived growth factor (PDGF), epidermal growth factor (EGF), angiogenin and their respective receptors constitutes one of the main targets for the design of new drugs in many pathologies,

This issue focuses on the signaling pathways of activators and inhibitors of angiogenesis in pathological conditions as well as to new pharmacological approach based on anti- or pro-angiogenic therapies.

Prof. Dr. Diego La Mendola
Prof. Dr. Maria Letizia Trincavelli
Prof. Dr. Claudia Martini
Guest Editors

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Keywords

blood vessels
angiogenic factors
trophic factors
angiogenesis biomarkers
signaling
cancers
neurodegeneration
heart diseases

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Published Papers (10 papers)

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Editorial

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4 pages, 207 KiB

Open AccessEditorial

Angiogenesis in Disease

by Diego La Mendola, Maria Letizia Trincavelli and Claudia Martini

Int. J. Mol. Sci. 2022, 23(18), 10962; https://doi.org/10.3390/ijms231810962 - 19 Sep 2022

Cited by 20 | Viewed by 3594

Abstract

Angiogenesis is a multi-step process by which new blood capillaries are formed starting from preexisting functional vessels [...] Full article

(This article belongs to the Special Issue Angiogenesis in Disease)

Research

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12 pages, 4985 KiB

Open AccessArticle

Ang–Tie Angiogenic Pathway Is Distinctively Expressed in Benign and Malignant Adrenocortical Tumors

by Sofia Oliveira, Sofia S. Pereira, Madalena M. Costa, Mariana P. Monteiro and Duarte Pignatelli

Int. J. Mol. Sci. 2022, 23(10), 5579; https://doi.org/10.3390/ijms23105579 - 17 May 2022

Cited by 2 | Viewed by 1953

Abstract

The differential diagnosis between adrenocortical adenomas (ACAs) and adrenocortical carcinomas (ACCs) relies on unspecific clinical, imaging and histological features, and, so far, no single molecular biomarker has proved to improve diagnostic accuracy. Similarly, prognostic factors have an insufficient capacity to predict the heterogeneity of ACC clinical outcomes, which consequently lead to inadequate treatment strategies. Angiogenesis is a biological process regulated by multiple signaling pathways, including VEGF and the Ang–Tie pathway. Many studies have stressed the importance of angiogenesis in cancer development and metastasis. In the present study, we evaluated the expression of VEGF and Ang–Tie pathway mediators in adrenocortical tumors (ACTs), with the ultimate goal of assessing whether these molecules could be useful biomarkers to improve diagnostic accuracy and/or prognosis prediction in ACC. The expression of the proteins involved in angiogenesis, namely CD34, VEGF, VEGF-R2, Ang1, Ang2, Tie1 and Tie2, was assessed by immunohistochemistry in ACC (n = 22), ACA with Cushing syndrome (n = 8) and non-functioning ACA (n = 13). ACC presented a significantly higher Ang1 and Ang2 expression when compared to ACA. Tie1 expression was higher in ACC with venous invasion and in patients with shorter overall survival. In conclusion, although none of these biomarkers showed to be useful for ACT diagnosis, the Ang–Tie pathway is active in ACT and may play a role in regulating ACT angiogenesis. Full article

(This article belongs to the Special Issue Angiogenesis in Disease)

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10 pages, 2928 KiB

Open AccessCommunication

Treatment with Angiotensin-(1-7) Prevents Development of Oral Papilloma Induced in K-ras Transgenic Mice

by Carolina Schere-Levy, Melisa Suberbordes, Darío M. Ferri, Marina Ayre, Albana Gattelli, Edith C. Kordon, Ana R. Raimondi and Thomas Walther

Int. J. Mol. Sci. 2022, 23(7), 3642; https://doi.org/10.3390/ijms23073642 - 26 Mar 2022

Cited by 1 | Viewed by 2605

Abstract

Oral Squamous Cell Carcinoma (OSCC) is the most common malignant cancer affecting the oral cavity. It is characterized by high morbidity and very few therapeutic options. Angiotensin (Ang)-(1-7) is a biologically active heptapeptide, generated predominantly from AngII (Ang-(1-8)) by the enzymatic activity of angiotensin-converting enzyme 2 (ACE 2). Previous studies have shown that Ang-(1-7) counterbalances AngII pro-tumorigenic actions in different pathophysiological settings, exhibiting antiproliferative and anti-angiogenic properties in cancer cells. However, the prevailing effects of Ang-(1-7) in the oral epithelium have not been established in vivo. Here, we used an inducible oral-specific mouse model, where the expression of a tamoxifen-inducible Cre recombinase (CreER^tam), which is under the control of the cytokeratin 14 promoter (K14-CreER^tam), induces the expression of the K-ras oncogenic variant KrasG12D (LSLK-ras^G12D). These mice develop highly proliferative squamous papilloma in the oral cavity and hyperplasia exclusively in oral mucosa within one month after tamoxifen treatment. Ang-(1-7) treated mice showed a reduced papilloma development accompanied by a significant reduction in cell proliferation and a decrease in pS6 positivity, the most downstream target of the PI3K/Akt/mTOR signaling route in oral papilloma. These results suggest that Ang-(1-7) may be a novel therapeutic target for OSCC. Full article

(This article belongs to the Special Issue Angiogenesis in Disease)

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14 pages, 8298 KiB

Open AccessArticle

The Effects of SRT1720 Treatment on Endothelial Cells Derived from the Lung and Bone Marrow of Young and Aged, Male and Female Mice

by Ushashi Chand Dadwal, Fazal Ur Rehman Bhatti, Olatundun Dupe Awosanya, Caio de Andrade Staut, Rohit U. Nagaraj, Anthony Joseph Perugini III, Nikhil Prasad Tewari, Conner Riley Valuch, Seungyup Sun, Stephen Kyle Mendenhall, Donghui Zhou, Sarah Lyn Mostardo, Rachel Jean Blosser, Jiliang Li and Melissa Ann Kacena

Int. J. Mol. Sci. 2021, 22(20), 11097; https://doi.org/10.3390/ijms222011097 - 14 Oct 2021

Cited by 5 | Viewed by 2278

Abstract

Angiogenesis is critical for successful fracture healing. Age-related alterations in endothelial cells (ECs) may cause impaired bone healing. Therefore, examining therapeutic treatments to improve angiogenesis in aging may enhance bone healing. Sirtuin 1 (SIRT1) is highly expressed in ECs and its activation is known to counteract aging. Here, we examined the effects of SRT1720 treatment (SIRT1 activator) on the growth and function of bone marrow and lung ECs (BMECs and LECs, respectively), derived from young (3–4 month) and old (20–24 month) mice. While aging did not alter EC proliferation, treatment with SRT1720 significantly increased proliferation of all LECs. However, SRT1720 only increased proliferation of old female BMECs. Vessel-like tube assays showed similar vessel-like structures between young and old LECs and BMECs from both male and female mice. SRT1720 significantly improved vessel-like structures in all LECs. No age, sex, or treatment differences were found in migration related parameters of LECs. In males, old BMECs had greater migration rates than young BMECs, whereas in females, old BMECs had lower migration rates than young BMECs. Collectively, our data suggest that treatment with SRT1720 appears to enhance the angiogenic potential of LECs irrespective of age or sex. However, its role in BMECs is sex- and age-dependent. Full article

(This article belongs to the Special Issue Angiogenesis in Disease)

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Review

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13 pages, 1163 KiB

Open AccessReview

PDGF/PDGFR: A Possible Molecular Target in Scleroderma Fibrosis

by Chiara Paolini, Silvia Agarbati, Devis Benfaremo, Matteo Mozzicafreddo, Silvia Svegliati and Gianluca Moroncini

Int. J. Mol. Sci. 2022, 23(7), 3904; https://doi.org/10.3390/ijms23073904 - 31 Mar 2022

Cited by 23 | Viewed by 3385

Abstract

Systemic sclerosis (SSc) is a clinically heterogeneous disorder of the connective tissue characterized by vascular alterations, immune/inflammatory manifestations, and organ fibrosis. SSc pathogenesis is complex and still poorly understood. Therefore, effective therapies are lacking and remain nonspecific and limited to disease symptoms. In the last few years, many molecular and cellular mediators of SSc fibrosis have been described, providing new potential options for targeted therapies. In this review: (i) we focused on the PDGF/PDGFR pathway as key signaling molecules in the development of tissue fibrosis; (ii) we highlighted the possible role of stimulatory anti-PDGFRα autoantibodies in the pathogenesis of SSc; (iii) we reported the most promising PDGF/PDGFR targeting therapies. Full article

(This article belongs to the Special Issue Angiogenesis in Disease)

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10 pages, 1048 KiB

Open AccessReview

Extracellular Environment-Controlled Angiogenesis, and Potential Application for Peripheral Nerve Regeneration

by Shingo Saio, Kanna Konishi, Hirofumi Hohjoh, Yuki Tamura, Teruaki Masutani, Arunasiri Iddamalgoda, Masamitsu Ichihashi, Hiroshi Hasegawa and Ken-ichi Mizutani

Int. J. Mol. Sci. 2021, 22(20), 11169; https://doi.org/10.3390/ijms222011169 - 16 Oct 2021

Cited by 20 | Viewed by 3524

Abstract

Endothelial cells acquire different phenotypes to establish functional vascular networks. Vascular endothelial growth factor (VEGF) signaling induces endothelial proliferation, migration, and survival to regulate vascular development, which leads to the construction of a vascular plexuses with a regular morphology. The spatiotemporal localization of angiogenic factors and the extracellular matrix play fundamental roles in ensuring the proper regulation of angiogenesis. This review article highlights how and what kinds of extracellular environmental molecules regulate angiogenesis. Close interactions between the vascular and neural systems involve shared molecular mechanisms to coordinate developmental and regenerative processes. This review article focuses on current knowledge about the roles of angiogenesis in peripheral nerve regeneration and the latest therapeutic strategies for the treatment of peripheral nerve injury. Full article

(This article belongs to the Special Issue Angiogenesis in Disease)

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14 pages, 2082 KiB

Open AccessReview

Angiogenin and Copper Crossing in Wound Healing

by Lorena Maria Cucci, Cristina Satriano, Tiziano Marzo and Diego La Mendola

Int. J. Mol. Sci. 2021, 22(19), 10704; https://doi.org/10.3390/ijms221910704 - 2 Oct 2021

Cited by 51 | Viewed by 8309

Abstract

Angiogenesis plays a key role in the wound healing process, involving the migration, growth, and differentiation of endothelial cells. Angiogenesis is controlled by a strict balance of different factors, and among these, the angiogenin protein plays a relevant role. Angiogenin is a secreted protein member of the ribonuclease superfamily that is taken up by cells and translocated to the nucleus when the process of blood vessel formation has to be promoted. However, the chemical signaling that activates the protein, normally present in the plasma, and the transport pathways through which the protein enters the cell are still largely unclear. Copper is also an angiogenic factor that regulates angiogenin expression and participates in the activation of common signaling pathways. The interaction between angiogenin and copper could be a relevant mechanism in regulating the formation of new blood vessel pathways and paving the way to the development of new drugs for chronic non-healing wounds. Full article

(This article belongs to the Special Issue Angiogenesis in Disease)

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17 pages, 1885 KiB

Open AccessReview

Netrin-1 in Glioblastoma Neovascularization: The New Partner in Crime?

by Ximena Vásquez, Pilar Sánchez-Gómez and Verónica Palma

Int. J. Mol. Sci. 2021, 22(15), 8248; https://doi.org/10.3390/ijms22158248 - 31 Jul 2021

Cited by 15 | Viewed by 4190

Abstract

Glioblastoma (GBM) is the most aggressive and common primary tumor of the central nervous system. It is characterized by having an infiltrating growth and by the presence of an excessive and aberrant vasculature. Some of the mechanisms that promote this neovascularization are angiogenesis and the transdifferentiation of tumor cells into endothelial cells or pericytes. In all these processes, the release of extracellular microvesicles by tumor cells plays an important role. Tumor cell-derived extracellular microvesicles contain pro-angiogenic molecules such as VEGF, which promote the formation of blood vessels and the recruitment of pericytes that reinforce these structures. The present study summarizes and discusses recent data from different investigations suggesting that Netrin-1, a highly versatile protein recently postulated as a non-canonical angiogenic ligand, could participate in the promotion of neovascularization processes in GBM. The relevance of determining the angiogenic signaling pathways associated with the interaction of Netrin-1 with its receptors is posed. Furthermore, we speculate that this molecule could form part of the microvesicles that favor abnormal tumor vasculature. Based on the studies presented, this review proposes Netrin-1 as a novel biomarker for GBM progression and vascularization. Full article

(This article belongs to the Special Issue Angiogenesis in Disease)

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24 pages, 1950 KiB

Open AccessReview

The “Angiogenic Switch” and Functional Resources in Cyclic Sports Athletes

by Olga V. Balberova, Evgeny V. Bykov, Natalia A. Shnayder, Marina M. Petrova, Oksana A. Gavrilyuk, Daria S. Kaskaeva, Irina A. Soloveva, Kirill V. Petrov, Elena Y. Mozheyko, German V. Medvedev and Regina F. Nasyrova

Int. J. Mol. Sci. 2021, 22(12), 6496; https://doi.org/10.3390/ijms22126496 - 17 Jun 2021

Cited by 10 | Viewed by 4834

Abstract

Regular physical activity in cyclic sports can influence the so-called “angiogenic switch”, which is considered as an imbalance between proangiogenic and anti-angiogenic molecules. Disruption of the synthesis of angiogenic molecules can be caused by local changes in tissues under the influence of excessive physical exertion and its consequences, such as chronic oxidative stress and associated hypoxia, metabolic acidosis, sports injuries, etc. A review of publications on signaling pathways that activate and inhibit angiogenesis in skeletal muscles, myocardium, lung, and nervous tissue under the influence of intense physical activity in cyclic sports. Materials: We searched PubMed, SCOPUS, Web of Science, Google Scholar, Clinical keys, and e-LIBRARY databases for full-text articles published from 2000 to 2020, using keywords and their combinations. Results: An important aspect of adaptation to training loads in cyclic sports is an increase in the number of capillaries in muscle fibers, which improves the metabolism of skeletal muscles and myocardium, as well as nervous and lung tissue. Recent studies have shown that myocardial endothelial cells not only respond to hemodynamic forces and paracrine signals from neighboring cells, but also take an active part in heart remodeling processes, stimulating the growth and contractility of cardiomyocytes or the production of extracellular matrix proteins in myofibroblasts. As myocardial vascularization plays a central role in the transition from adaptive heart hypertrophy to heart failure, further study of the signaling mechanisms involved in the regulation of angiogenesis in the myocardium is important in sports practice. The study of the “angiogenic switch” problem in the cerebrovascular and cardiovascular systems allows us to claim that the formation of new vessels is mediated by a complex interaction of all growth factors. Although the lungs are one of the limiting systems of the body in cyclic sports, their response to high-intensity loads and other environmental stresses is often overlooked. Airway epithelial cells are the predominant source of several growth factors throughout lung organogenesis and appear to be critical for normal alveolarization, rapid alveolar proliferation, and normal vascular development. There are many controversial questions about the role of growth factors in the physiology and pathology of the lungs. The presented review has demonstrated that when doing sports, it is necessary to give a careful consideration to the possible positive and negative effects of growth factors on muscles, myocardium, lung tissue, and brain. Primarily, the “angiogenic switch” is important in aerobic sports (long distance running). Conclusions: Angiogenesis is a physiological process of the formation of new blood capillaries, which play an important role in the functioning of skeletal muscles, myocardium, lung, and nervous tissue in athletes. Violation of the “angiogenic switch” as a balance between proangiogenic and anti-angiogenic molecules can lead to a decrease in the functional resources of the nervous, musculoskeletal, cardiovascular, and respiratory systems in athletes and, as a consequence, to a decrease in sports performance. Full article

(This article belongs to the Special Issue Angiogenesis in Disease)

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10 pages, 6273 KiB

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Dysregulation of the Renin-Angiotensin-Aldosterone System (RAA) in Patients Infected with SARS-CoV-2-Possible Clinical Consequences

by Agnieszka Dettlaff-Pokora and Julian Swierczynski

Int. J. Mol. Sci. 2021, 22(9), 4503; https://doi.org/10.3390/ijms22094503 - 26 Apr 2021

Cited by 14 | Viewed by 4395

Abstract

SARS-CoV-2 impairs the renin-angiotensin-aledosterone system via binding ACE2 enzyme. ACE2 plays a key role in the biosynthesis of angiotensin (1-7), catalyzing the conversion of angiotensin 2 into angiotensin (1-7) and the reaction of angiotensin synthesis (1-9), from which angiotensin is (1-7) produced under the influence of ACE (Angiotensin-Converting Enzyme). Angiotensin 2 is a potent vasoconstrictor and atherogenic molecule converted by ACE2 to reducing inflammation and vasodilating in action angiotensin (1-7). Angiotensin (1-9), that is a product of angiotensin 1 metabolism and precursor of angiotensin (1-7), also exerts cell protective properties. Balance between angiotensin 2 and angiotensin (1-7) regulates blood pressure and ACE2 plays a critical role in this balance. ACE2, unlike ACE, is not inhibited by ACE inhibitors at the doses used in humans during the treatment of arterial hypertension. Membrane ACE2 is one of the receptors that allows SARS-CoV-2 to enter the host cells. ACE2 after SARS-CoV-2 binding is internalized and degraded. Hence ACE2 activity on the cell surface is reduced leading to increase the concentration of angiotensin 2 and decrease the concentration of angiotensin (1-7). Disturbed angiotensins metabolism, changes in ratio between angiotensins with distinct biological activities leading to domination of atherogenic angiotensin 2 can increase the damage to the lungs. Full article

(This article belongs to the Special Issue Angiogenesis in Disease)

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