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Molecular Mechanisms of Angiogenesis in Health and Diseases

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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 May 2022) | Viewed by 38210

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Dr. Adel B. Elmoselhi

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Guest Editor

1. Basic Medical Sciences Department, College of Medicine, University of Sharjah, Sharjah, UAE
2. Physiology Department, Migichan State University, East Lansing, MI, USA
Interests: cardiovascular diseases; medical education; angiogenesis

Prof. Dr. Miguel Ángel Medina Torres

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Guest Editor

Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Universidad de Málaga, Andalucía Tech, E-29071 Málaga, Spain
Interests: angiogenesis; tumor metabolism; membrane transporters: plasma membrane redox; rare diseases; systems biology; polyamine and biogenic amine metabolism; metabolic modelling
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Dear Colleagues,

Angiogenesis is an essential process for tissue survival, both physiologically during fetus development and wound healing, as well as pathologically in a plethora of diseases such as cancer, obesity, diabetic retinopathy, endometriosis, and skin and bone diseases. More recently, angiogenesis has also been shown to have an important role in tissue adaptation under microgravity and other space environments. The new capillaries that develop in angiogenesis sprout from existing vessels and are usually initiated via hypoxia and a lack of nutrients in the surrounding tissues. Angiogenesis is facilitated by pro-angiogenic factors such as VEGF and FGFs, among other mechanisms, and inhibited by anti-angiogenic factors. The therapeutic potential of regulating angiogenesis is tremendous since it is capable of treating major highly prevalent fatal diseases such as ischemic heart disease, stroke, and cancers. For this reason and others, the field of angiogenesis has been growing exponentially in the last fifty years; however, it is still far from reaching its potential. In this Special Issue, the aims are to provide an update on molecular mechanisms of angiogenesis relevant to various aspects in health and diseases, shed some light on the current development of angiogenesis-related diagnostic and therapeutic approaches, and to point out possible future directions.

Dr. Adel B. Elmoselhi
Prof. Dr. Miguel Ángel Medina Torres
Guest Editor

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Keywords

angiogenesis
endothelial cells
vascular endothelial growth factors (VEGFs)
pro-angiogenic factors
anti-angiogenic factors
hypoxia
cancer
ischemic heart diseases
obesity
diabetic retinopathy

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Published Papers (9 papers)

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Editorial

Jump to: Research, Review

2 pages, 166 KiB

Open AccessEditorial

Advantages of Understanding the Molecular Mechanisms of Angiogenesis in Various Physiological and Pathological Conditions

by Adel B. Elmoselhi

Int. J. Mol. Sci. 2023, 24(6), 5412; https://doi.org/10.3390/ijms24065412 - 12 Mar 2023

Cited by 2 | Viewed by 1196

Abstract

The aim of this Special Issue is to highlight the diverse benefits and approaches to studying angiogenesis in various physiological and pathological conditions, such as damaged tissues, impaired embryonic development, cancer progression, and cardiovascular and chronic inflammatory disorders [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms of Angiogenesis in Health and Diseases)

Research

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13 pages, 2133 KiB

Open AccessArticle

Recombinant Human Arresten and Canstatin Inhibit Angiogenic Behaviors of HUVECs via Inhibiting the PI3K/Akt Signaling Pathway

by Lingyu Zhu, Zitao Guo, Ji Zhang, Yuliang Yang, Chunyu Liu, Liang Zhang, Zhenghua Gu, Youran Li, Zhongyang Ding and Guiyang Shi

Int. J. Mol. Sci. 2022, 23(16), 8995; https://doi.org/10.3390/ijms23168995 - 12 Aug 2022

Cited by 7 | Viewed by 2281

Abstract

Angiogenetic inhibitors are crucial in tumor therapy, and endogenous angiogenesis inhibitors have attracted considerable attention due to their effectiveness, safety, and multi-targeting ability. Arresten and canstatin, which have anti-angiogenesis effects, are the c-terminal fragments of the α1 and α2 chains of type IV collagen, respectively. In this study, human arresten and canstatin were recombinantly expressed in Escherichia coli (E. coli), and their effects on the proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs) were evaluated. Regarding the cell cycle distribution test and 5-ethynyl-2′-deoxyuridine (EdU) assays, arresten and canstatin could repress the proliferation of HUVECs at a range of concentrations. Transwell assay indicated that the migration of HUVECs was significantly decreased in the presence of arresten and canstatin, while tube formation assays suggested that the total tube length and junction number of HUVECs were significantly inhibited by these two proteins; moreover, they could also reduce the expression of vascular endothelial growth factor (VEGF) and the phosphorylation levels of PI3K and Akt, which indicated that the activation of the 3-kinase/serine/threonine-kinase (PI3K/Akt) signaling pathway was inhibited. These findings may have important implications for the soluble recombinant expression of human arresten and canstatin, and for the related therapy of cancer. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Angiogenesis in Health and Diseases)

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13 pages, 3788 KiB

Open AccessArticle

Glycation of Tie-2 Inhibits Angiopoietin-1 Signaling Activation and Angiopoietin-1-Induced Angiogenesis

by Haiyan Zhou, Tangting Chen, Yongjie Li, Jingcan You, Xin Deng, Ni Chen, Tian Li, Youkun Zheng, Rong Li, Mao Luo, Jianbo Wu and Liqun Wang

Int. J. Mol. Sci. 2022, 23(13), 7137; https://doi.org/10.3390/ijms23137137 - 27 Jun 2022

Cited by 10 | Viewed by 2130

Abstract

The impairment of the angiopoietin-1 (Ang-1)/Tie-2 signaling pathway has been thought to play a critical role in diabetic complications. However, the underlying mechanisms remain unclear. The present study aims to investigate the effects of Tie-2 glycation on Ang-1 signaling activation and Ang-1-induced angiogenesis. We identified that Tie-2 was modified by advanced glycation end products (AGEs) in aortae derived from high fat diet (HFD)-fed mice and in methylglyoxal (MGO)-treated human umbilical vein endothelial cells (HUVECs). MGO-induced Tie-2 glycation significantly inhibited Ang-1-evoked Tie-2 and Akt phosphorylation and Ang-1-regulated endothelial cell migration and tube formation, whereas the blockade of AGE formation by aminoguanidine remarkably rescued Ang-1 signaling activation and Ang-1-induced angiogenesis in vitro. Furthermore, MGO treatment markedly increased AGE cross-linking of Tie-2 in cultured aortae ex vivo and MGO-induced Tie-2 glycation also significantly decreased Ang-1-induced vessel outgrow from aortic rings. Collectively, these data suggest that Tie-2 may be modified by AGEs in diabetes mellitus and that Tie-2 glycation inhibits Ang-1 signaling activation and Ang-1-induced angiogenesis. This may provide a novel mechanism for Ang-1/Tie-2 signal dysfunction and angiogenesis failure in diabetic ischaemic diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Angiogenesis in Health and Diseases)

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17 pages, 5781 KiB

Open AccessArticle

A Novel High Content Angiogenesis Assay Reveals That Lacidipine, L-Type Calcium Channel Blocker, Induces In Vitro Vascular Lumen Expansion

by Dorota A. Nawrot, Lutfiye Yildiz Ozer and Ayman Al Haj Zen

Int. J. Mol. Sci. 2022, 23(9), 4891; https://doi.org/10.3390/ijms23094891 - 28 Apr 2022

Cited by 7 | Viewed by 2873

Abstract

Angiogenesis is a critical cellular process toward establishing a functional circulatory system capable of delivering oxygen and nutrients to the tissue in demand. In vitro angiogenesis assays represent an important tool for elucidating the biology of blood vessel formation and for drug discovery applications. Herein, we developed a novel, high content 2D angiogenesis assay that captures endothelial morphogenesis’s cellular processes, including lumen formation. In this assay, endothelial cells form luminized vascular-like structures in 48 h. The assay was validated for its specificity and performance. Using the optimized assay, we conducted a phenotypic screen of a library containing 150 FDA-approved cardiovascular drugs to identify modulators of lumen formation. The screening resulted in several L-type calcium channel blockers being able to expand the lumen space compared to controls. Among these blockers, Lacidipine was selected for follow-up studies. We found that the endothelial cells treated with Lacidipine showed enhanced activity of caspase-3 in the luminal space. Pharmacological inhibition of caspase activity abolished the Lacidipine-enhancing effect on lumen formation, suggesting the involvement of apoptosis. Using a Ca²⁺ biosensor, we found that Lacipidine reduces the intracellular Ca²⁺ oscillations amplitude in the endothelial cells at the early stage, whereas Lacidipine blocks these Ca²⁺ oscillations completely at the late stage. The inhibition of MLCK exhibits a phenotype of lumen expansion similar to that of Lacidipine. In conclusion, this study describes a novel high-throughput phenotypic assay to study angiogenesis. Our findings suggest that calcium signalling plays an essential role during lumen morphogenesis. L-type Ca²⁺ channel blockers could be used for more efficient angiogenesis-mediated therapies. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Angiogenesis in Health and Diseases)

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15 pages, 3402 KiB

Open AccessArticle

Synergistic Anti-Angiogenic Effect of Combined VEGFR Kinase Inhibitors, Lenvatinib, and Regorafenib: A Therapeutic Potential for Breast Cancer

by Khuloud Bajbouj, Rizwan Qaisar, Mohammed A. Alshura, Zeinab Ibrahim, Mohamad B. Alebaji, Amenah W. Al Ani, Hanadi M. Janajrah, Mariah M. Bilalaga, Abdelrahman I. Omara, Rebal S. Abou Assaleh, Maha M. Saber-Ayad and Adel B. Elmoselhi

Int. J. Mol. Sci. 2022, 23(8), 4408; https://doi.org/10.3390/ijms23084408 - 16 Apr 2022

Cited by 12 | Viewed by 3603

Abstract

Background: Breast cancer currently affects more than two million women worldwide, and its incidence is steadily increasing. One of the most essential factors of invasion and metastasis of breast cancer cells is angiogenesis and non-angiogenic vascularization. Lenvatinib and Regorafenib share the same anti-angiogenic effect by inhibiting vascular endothelial growth factor receptors (VEGFRs subtypes 1 to 3) and have been approved for treating different types of cancer. Methods: We investigated Lenvatinib and Regorafenib effects on a well-established in-vitro model of breast cancer using MCF-7 (estrogen, progesterone receptor-positive, and HER2-negative), MDA-MB-231 (triple negative), as well as Human Umbilical Vascular Endothelial Cell line (HUVEC) cell lines. We performed the cell viability assay on four groups of cells, which included a control group, a Lenvatinib treated only group, a Regorafenib treated only group, and a group treated with a combination of both drugs at 24, 48, and 72 h. Data were analyzed as means ± standard deviation, and the drug–drug interactions with Compusyn software. Cellular migration assay, tube formation assay, and Western blots were conducted to determine the functional and the protein expression of downstream signals such as Caspase-9, anti-apoptotic Survivin, P-ERK, and total-ERK in the control and treatment groups. Results: MCF-7 cells showed a reduction in cell survival rates with higher dosing and longer incubation periods with each drug and with the combination of drugs. A synergistic interaction was identified (CI < 1) with both drugs on MCF7 at different dose combinations and at a higher dose in MDA-MB-231 cells. Furthermore, there was a marked decrease in the anti-angiogenic effect of both drugs in tube formation assay using MDA-MB-231 cells and survivin protein expression in MCF-7, and those antitumor markers showed a better outcome in drug combination than the use of each drug alone. Conclusion: Our result is the first to report the synergistic anti-angiogenic potential of combination therapy of Lenvatinib and Regorafenib. Therefore, it shows their therapeutic potential in breast cancer, including the aggressive types. Further studies are warranted to confirm and explore this therapeutic approach. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Angiogenesis in Health and Diseases)

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22 pages, 3908 KiB

Open AccessArticle

In Vitro Angiogenesis Inhibition and Endothelial Cell Growth and Morphology

by Arlinda Ljoki, Tanzila Aslam, Tina Friis, Ragnhild G. Ohm and Gunnar Houen

Int. J. Mol. Sci. 2022, 23(8), 4277; https://doi.org/10.3390/ijms23084277 - 12 Apr 2022

Cited by 5 | Viewed by 3603

Abstract

A co-culture assay with human umbilical vein endothelial cells (HUVECs) and normal human dermal fibroblasts (NHDFs) was used to study whether selected angiogenesis inhibitors were able to inhibit differentiation and network formation of HUVECs in vitro. The effect of the inhibitors was determined by the morphology and the calculated percentage area covered by HUVECs. Neutralizing VEGF with avastin and polyclonal goat anti-VEGF antibody and inhibiting VEGFR2 with sorafenib and vatalanib resulted in the formation of HUVEC clusters of variable sizes as a result of inhibited EC differentiation. Furthermore, numerous inhibitors of the VEGF signaling pathways were tested for their effect on the growth and differentiation of HUVECs. The effects of these inhibitors did not reveal a cluster morphology, either individually or when combined to block VEGFR2 downstream pathways. Only the addition of N-methyl-p-bromolevamisole revealed a similar morphology as when targeting VEGF and VEGFR2, meaning it may have an inhibitory influence directly on VEGFR signaling. Additionally, several nuclear receptor ligands and miscellaneous compounds that might affect EC growth and differentiation were tested, but only dexamethasone gave rise to cluster formation similarly to VEGF-neutralizing compounds. These results point to a link between angiogenesis, HUVEC differentiation and glucocorticoid receptor activation. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Angiogenesis in Health and Diseases)

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Review

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25 pages, 1991 KiB

Open AccessReview

Emerging Anti-Inflammatory Pharmacotherapy and Cell-Based Therapy for Lymphedema

by Ryohei Ogino, Tomoharu Yokooji, Maiko Hayashida, Shota Suda, Sho Yamakawa and Kenji Hayashida

Int. J. Mol. Sci. 2022, 23(14), 7614; https://doi.org/10.3390/ijms23147614 - 9 Jul 2022

Cited by 12 | Viewed by 4611

Abstract

Secondary lymphedema is a common complication of lymph node dissection or radiation therapy for cancer treatment. Conventional therapies such as compression sleeve therapy, complete decongestive physiotherapy, and surgical therapies decrease edema; however, they are not curative because they cannot modulate the pathophysiology of lymphedema. Recent advances reveal that the activation and accumulation of CD4+ T cells are key in the development of lymphedema. Based on this pathophysiology, the efficacy of pharmacotherapy (tacrolimus, anti-IL-4/IL-13 antibody, or fingolimod) and cell-based therapy for lymphedema has been demonstrated in animal models and pilot studies. In addition, mesenchymal stem/stromal cells (MSCs) have attracted attention as candidates for cell-based lymphedema therapy because they improve symptoms and decrease edema volume in the long term with no serious adverse effects in pilot studies. Furthermore, MSC transplantation promotes functional lymphatic regeneration and improves the microenvironment in animal models. In this review, we focus on inflammatory cells involved in the pathogenesis of lymphedema and discuss the efficacy and challenges of pharmacotherapy and cell-based therapies for lymphedema. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Angiogenesis in Health and Diseases)

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19 pages, 1326 KiB

Open AccessReview

The Plasminogen–Activator Plasmin System in Physiological and Pathophysiological Angiogenesis

by Asmaa Anwar Ismail, Baraah Tariq Shaker and Khalid Bajou

Int. J. Mol. Sci. 2022, 23(1), 337; https://doi.org/10.3390/ijms23010337 - 29 Dec 2021

Cited by 58 | Viewed by 6973

Abstract

Angiogenesis is a process associated with the migration and proliferation of endothelial cells (EC) to form new blood vessels. It is involved in various physiological and pathophysiological conditions and is controlled by a wide range of proangiogenic and antiangiogenic molecules. The plasminogen activator–plasmin system plays a major role in the extracellular matrix remodeling process necessary for angiogenesis. Urokinase/tissue-type plasminogen activators (uPA/tPA) convert plasminogen into the active enzyme plasmin, which in turn activates matrix metalloproteinases and degrades the extracellular matrix releasing growth factors and proangiogenic molecules such as the vascular endothelial growth factor (VEGF-A). The plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of uPA and tPA, thereby an inhibitor of pericellular proteolysis and intravascular fibrinolysis, respectively. Paradoxically, PAI-1, which is expressed by EC during angiogenesis, is elevated in several cancers and is found to promote angiogenesis by regulating plasmin-mediated proteolysis and by promoting cellular migration through vitronectin. The urokinase-type plasminogen activator receptor (uPAR) also induces EC cellular migration during angiogenesis via interacting with signaling partners. Understanding the molecular functions of the plasminogen activator plasmin system and targeting angiogenesis via blocking serine proteases or their interactions with other molecules is one of the major therapeutic strategies scientists have been attracted to in controlling tumor growth and other pathological conditions characterized by neovascularization. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Angiogenesis in Health and Diseases)

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15 pages, 1546 KiB

Open AccessReview

Angiogenesis in Chronic Inflammatory Skin Disorders

by Hyun Ji Lee, Yong Jun Hong and Miri Kim

Int. J. Mol. Sci. 2021, 22(21), 12035; https://doi.org/10.3390/ijms222112035 - 7 Nov 2021

Cited by 101 | Viewed by 9261

Abstract

Angiogenesis, the growth of new blood vessels from preexisting vessels, is associated with inflammation in various pathological conditions. Well-known angiogenetic factors include vascular endothelial growth factor (VEGF), angiopoietins, platelet-derived growth factor, transforming growth factor-β, and basic fibroblast growth factor. Yes-associated protein 1 (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) have recently been added to an important angiogenic factor. Accumulating evidence indicates associations between angiogenesis and chronic inflammatory skin diseases. Angiogenesis is deeply involved in the pathogenesis of psoriasis. VEGF, angiopoietins, tumor necrosis factor-a, interleukin-8, and interleukin-17 are unregulated in psoriasis and induce angiogenesis. Angiogenesis may be involved in the pathogenesis of atopic dermatitis, and in particular, mast cells are a major source of VEGF expression. Angiogenesis is an essential process in rosacea, which is induced by LL-37 from a signal cascade by microorganisms, VEGF, and MMP-3 from mast cells. In addition, angiogenesis by increased VEGF has been reported in chronic urticaria and hidradenitis suppurativa. The finding that VEGF is expressed in inflammatory skin lesions indicates that inhibition of angiogenesis is a useful strategy for treatment of chronic, inflammatory skin disorders. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Angiogenesis in Health and Diseases)

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