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Arteriogenesis, Angiogenesis and Vascular Remodeling

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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 (30 April 2023) | Viewed by 18622

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Special Issue Editors

Prof. Dr. Elisabeth Deindl

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Guest Editor

Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
Interests: cardiovascular research; immunology
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Paul Quax

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Guest Editor

1. Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
2. Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
Interests: experimental vascular medicine; blood vessel; arteriogenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Arteriogenesis, also frequently called collateral formation or even therapeutic angiogenesis, comprises those processes that lead to the formation and growth of collateral blood vessels that can act as natural bypasses to restore blood flow to distal tissues in occluded arteries. Both in coronary occlusive artery diseases as well as in peripheral occlusive arterial disease, arteriogenesis may play an important role in the restoration of blood flow.

Blood flow restoration in arteries affected by atherosclerosis can also be achieved by balloon angioplasty, with or without stenting, or bypass surgery. Unfortunately, these interventions may also lead to the induction of vascular remodeling leading to intimal hyperplasia and re-occlusion of the treated vessels. In these inflammatory-driven vascular remodeling processes, many cell types, both vascular cells and immune cells, many cytokines and growth factors, as well as various noncoding RNAs or progenitor cells may be involved. Consequently, many questions regarding the exact molecular mechanisms involved in the regulation of the vascular remodeling response in arteriogenesis and angiogenesis still need to be answered, and these answers will contribute to defining new therapeutic options.

Despite the big clinical potential and the many promising clinical trials on arteriogenesis and therapeutic angiogenesis, the exact molecular mechanisms involved in the multifactorial processes of vascular remodeling related to arteriogenesis and angiogenesis are still not completely understood.

This Special Issue of International Journal of Molecular Sciences is devoted to all molecular aspects of arteriogenesis and collateral formation. It will contain articles that collectively provide a balanced, state-of-the-art views on various aspects of arteriogenesis and the underlying regulation of vascular remodeling. We seek submissions of high-quality articles on all aspects of arteriogenesis, including but not limited to regulatory mechanisms, the cell types involved, state-of-the-art models and therapeutic options.

Potential topics include, but are not limited to, the following:

Genetic and environmental mechanisms controlling formation and maintenance of the native collateral circulation
Mechanisms controlling pathophysiological formation and maintenance of the angiogenic blood vessels
Mechanisms controlling pathophysiological vascular remodeling
Arteriogenesis, therapeutic angiogenesis and peripheral arterial disease
The formation of collateral arterial networks: insights from the developing embryo
Multiple pathways converge in the development of a collateral circulation
Arteriogenesis and collateral formation
Cell and gene therapy in peripheral arterial disease
Epigenetic and epitranscriptomic mechanisms in arteriogenesis, angiogenesis and vascular remodeling
Non-coding rna in vascular remodeling during arteriogenesis and angiogenesis
Bone marrow derived cells in arteriogenesis and therapeutic angiogenesis
Local and sustained drug delivery in arteriogenesis
Mechanisms controlling arteriogenesis, angiogenesis and vascular remodeling

Prof. Dr. Elisabeth Deindl
Prof. Dr. Paul Quax
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

arteriogenesis
angiogenesis
collateral formation
peripheral arterial disease
vascular remodeling
atherosclerosis
restenosis
intimal hyperplasia
vein grafting
cardiovascular diseases
cell and gene therapy
critical limb ischemia
therapeutic angiogenesis
collateral circulation
drug delivery

Published Papers (10 papers)

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Research

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13 pages, 2392 KiB

Open AccessArticle

Exploring the Effects of Human Bone Marrow-Derived Mononuclear Cells on Angiogenesis In Vitro

by Judith A. H. M. Peeters, Hendrika A. B. Peters, Anique J. Videler, Jaap F. Hamming, Abbey Schepers and Paul H. A. Quax

Int. J. Mol. Sci. 2023, 24(18), 13822; https://doi.org/10.3390/ijms241813822 - 07 Sep 2023

Viewed by 814

Abstract

Cell therapies involving the administration of bone marrow-derived mononuclear cells (BM-MNCs) for patients with chronic limb-threatening ischemia (CLTI) have shown promise; however, their overall effectiveness lacks evidence, and the exact mechanism of action remains unclear. In this study, we examined the angiogenic effects of well-controlled human bone marrow cell isolates on endothelial cells. The responses of endothelial cell proliferation, migration, tube formation, and aortic ring sprouting were analyzed in vitro, considering both the direct and paracrine effects of BM cell isolates. Furthermore, we conducted these investigations under both normoxic and hypoxic conditions to simulate the ischemic environment. Interestingly, no significant effect on the angiogenic response of human umbilical vein endothelial cells (HUVECs) following treatment with BM-MNCs was observed. This study fails to provide significant evidence for angiogenic effects from human bone marrow cell isolates on human endothelial cells. These in vitro experiments suggest that the potential benefits of BM-MNC therapy for CLTI patients may not involve endothelial cell angiogenesis. Full article

(This article belongs to the Special Issue Arteriogenesis, Angiogenesis and Vascular Remodeling)

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9 pages, 2318 KiB

Open AccessCommunication

Rag1 Deficiency Impairs Arteriogenesis in Mice

by Konda Kumaraswami, Christoph Arnholdt, Elisabeth Deindl and Manuel Lasch

Int. J. Mol. Sci. 2023, 24(16), 12839; https://doi.org/10.3390/ijms241612839 - 16 Aug 2023

Viewed by 847

Abstract

Increasing evidence suggests that lymphocytes play distinct roles in inflammation-induced tissue remodeling and tissue damage. Arteriogenesis describes the growth of natural bypasses from pre-existing collateral arteries. This process compensates for the loss of artery function in occlusive arterial diseases. The role of innate immune cells is widely understood in the process of arteriogenesis, whereas the role of lymphocytes remains unclear and is the subject of the present study. To analyze the role of lymphocytes, we induced arteriogenesis in recombination activating gene-1 (Rag1) knockout (KO) mice by unilateral ligation of the femoral artery. The lack of functional lymphocytes in Rag1 KO mice resulted in reduced perfusion recovery as shown by laser Doppler imaging. Additionally, immunofluorescence staining revealed a reduced vascular cell proliferation along with a smaller inner luminal diameter in Rag1 KO mice. The perivascular macrophage polarization around the growing collateral arteries was shifted to more pro-inflammatory M1-like polarized macrophages. Together, these data suggest that lymphocytes are crucial for arteriogenesis by modulating perivascular macrophage polarization. Full article

(This article belongs to the Special Issue Arteriogenesis, Angiogenesis and Vascular Remodeling)

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16 pages, 11770 KiB

Open AccessArticle

Computational Fluid Dynamics (CFD) Model for Analysing the Role of Shear Stress in Angiogenesis in Rheumatoid Arthritis

by Malaika K. Motlana and Malebogo N. Ngoepe

Int. J. Mol. Sci. 2023, 24(9), 7886; https://doi.org/10.3390/ijms24097886 - 26 Apr 2023

Viewed by 1388

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterised by an attack on healthy cells in the joints. Blood flow and wall shear stress are crucial in angiogenesis, contributing to RA’s pathogenesis. Vascular endothelial growth factor (VEGF) regulates angiogenesis, and shear stress is a surrogate for VEGF in this study. Our objective was to determine how shear stress correlates with the location of new blood vessels and RA progression. To this end, two models were developed using computational fluid dynamics (CFD). The first model added new blood vessels based on shear stress thresholds, while the second model examined the entire blood vessel network. All the geometries were based on a micrograph of RA blood vessels. New blood vessel branches formed in low shear regions (0.840–1.260 Pa). This wall-shear-stress overlap region at the junctions was evident in all the models. The results were verified quantitatively and qualitatively. Our findings point to a relationship between the development of new blood vessels in RA, the magnitude of wall shear stress and the expression of VEGF. Full article

(This article belongs to the Special Issue Arteriogenesis, Angiogenesis and Vascular Remodeling)

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19 pages, 3706 KiB

Open AccessArticle

Induction of Angiogenesis by Genetically Modified Human Umbilical Cord Blood Mononuclear Cells

by Dilara Z. Gatina, Ilnaz M. Gazizov, Margarita N. Zhuravleva, Svetlana S. Arkhipova, Maria A. Golubenko, Marina O. Gomzikova, Ekaterina E. Garanina, Rustem R. Islamov, Albert A. Rizvanov and Ilnur I. Salafutdinov

Int. J. Mol. Sci. 2023, 24(5), 4396; https://doi.org/10.3390/ijms24054396 - 23 Feb 2023

Cited by 2 | Viewed by 1616

Abstract

Stimulating the process of angiogenesis in treating ischemia-related diseases is an urgent task for modern medicine, which can be achieved through the use of different cell types. Umbilical cord blood (UCB) continues to be one of the attractive cell sources for transplantation. The goal of this study was to investigate the role and therapeutic potential of gene-engineered umbilical cord blood mononuclear cells (UCB-MC) as a forward-looking strategy for the activation of angiogenesis. Adenovirus constructs Ad-VEGF, Ad-FGF2, Ad-SDF1α, and Ad-EGFP were synthesized and used for cell modification. UCB-MCs were isolated from UCB and transduced with adenoviral vectors. As part of our in vitro experiments, we evaluated the efficiency of transfection, the expression of recombinant genes, and the secretome profile. Later, we applied an in vivo Matrigel plug assay to assess engineered UCB-MC’s angiogenic potential. We conclude that hUCB-MCs can be efficiently modified simultaneously with several adenoviral vectors. Modified UCB-MCs overexpress recombinant genes and proteins. Genetic modification of cells with recombinant adenoviruses does not affect the profile of secreted pro- and anti-inflammatory cytokines, chemokines, and growth factors, except for an increase in the synthesis of recombinant proteins. hUCB-MCs genetically modified with therapeutic genes induced the formation of new vessels. An increase in the expression of endothelial cells marker (CD31) was revealed, which correlated with the data of visual examination and histological analysis. The present study demonstrates that gene-engineered UCB-MC can be used to stimulate angiogenesis and possibly treat cardiovascular disease and diabetic cardiomyopathy. Full article

(This article belongs to the Special Issue Arteriogenesis, Angiogenesis and Vascular Remodeling)

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14 pages, 2495 KiB

Open AccessArticle

Non-Muscle MLCK Contributes to Endothelial Cell Hyper-Proliferation through the ERK Pathway as a Mechanism for Vascular Remodeling in Pulmonary Hypertension

by Mariam Anis, Janae Gonzales, Rachel Halstrom, Noman Baig, Cat Humpal, Regaina Demeritte, Yulia Epshtein, Jeffrey R. Jacobson and Dustin R. Fraidenburg

Int. J. Mol. Sci. 2022, 23(21), 13641; https://doi.org/10.3390/ijms232113641 - 07 Nov 2022

Cited by 2 | Viewed by 1849

Abstract

Pulmonary arterial hypertension (PAH) is characterized by endothelial dysfunction, uncontrolled proliferation and migration of pulmonary arterial endothelial cells leading to increased pulmonary vascular resistance resulting in great morbidity and poor survival. Bone morphogenetic protein receptor II (BMPR2) plays an important role in the pathogenesis of PAH as the most common genetic mutation. Non-muscle myosin light chain kinase (nmMLCK) is an essential component of the cellular cytoskeleton and recent studies have shown that increased nmMLCK activity regulates biological processes in various pulmonary diseases such as asthma and acute lung injury. In this study, we aimed to discover the role of nmMLCK in the proliferation and migration of pulmonary arterial endothelial cells (HPAECs) in the pathogenesis of PAH. We used two cellular models relevant to the pathobiology of PAH including BMPR2 silenced and vascular endothelial growth factor (VEGF) stimulated HPAECs. Both models demonstrated an increase in nmMLCK activity along with a robust increase in cellular proliferation, inflammation, and cellular migration. The upregulated nmMLCK activity was also associated with increased ERK expression pointing towards a potential integral cytoplasmic interaction. Mechanistically, we confirmed that when nmMLCK is inhibited by MLCK selective inhibitor (ML-7), proliferation and migration are attenuated. In conclusion, our results demonstrate that nmMLCK upregulation in association with increased ERK expression may contribute to the pathogenesis of PAHby stimulating cellular proliferation and migration. Full article

(This article belongs to the Special Issue Arteriogenesis, Angiogenesis and Vascular Remodeling)

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15 pages, 2716 KiB

Open AccessArticle

Cobra Venom Factor Boosts Arteriogenesis in Mice

by Philipp Götz, Sharon O. Azubuike-Osu, Anna Braumandl, Christoph Arnholdt, Matthias Kübler, Lisa Richter, Manuel Lasch, Lisa Bobrowski, Klaus T. Preissner and Elisabeth Deindl

Int. J. Mol. Sci. 2022, 23(15), 8454; https://doi.org/10.3390/ijms23158454 - 30 Jul 2022

Cited by 2 | Viewed by 2056

Abstract

Arteriogenesis, the growth of natural bypass blood vessels, can compensate for the loss of arteries caused by vascular occlusive diseases. Accordingly, it is a major goal to identify the drugs promoting this innate immune system-driven process in patients aiming to save their tissues and life. Here, we studied the impact of the Cobra venom factor (CVF), which is a C3-like complement-activating protein that induces depletion of the complement in the circulation in a murine hind limb model of arteriogenesis. Arteriogenesis was induced in C57BL/6J mice by femoral artery ligation (FAL). The administration of a single dose of CVF (12.5 µg) 24 h prior to FAL significantly enhanced the perfusion recovery 7 days after FAL, as shown by Laser Doppler imaging. Immunofluorescence analyses demonstrated an elevated number of proliferating (BrdU⁺) vascular cells, along with an increased luminal diameter of the grown collateral vessels. Flow cytometric analyses of the blood samples isolated 3 h after FAL revealed an elevated number of neutrophils and platelet-neutrophil aggregates. Giemsa stains displayed augmented mast cell recruitment and activation in the perivascular space of the growing collaterals 8 h after FAL. Seven days after FAL, we found more CD68⁺/MRC-1⁺ M2-like polarized pro-arteriogenic macrophages around growing collaterals. These data indicate that a single dose of CVF boosts arteriogenesis by catalyzing the innate immune reactions, relevant for collateral vessel growth. Full article

(This article belongs to the Special Issue Arteriogenesis, Angiogenesis and Vascular Remodeling)

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15 pages, 2721 KiB

Open AccessArticle

MicroRNA-30b Is Both Necessary and Sufficient for Interleukin-21 Receptor-Mediated Angiogenesis in Experimental Peripheral Arterial Disease

by Tao Wang, Liang Yang, Mingjie Yuan, Charles R. Farber, Rosanne Spolski, Warren J. Leonard, Vijay C. Ganta and Brian H. Annex

Int. J. Mol. Sci. 2022, 23(1), 271; https://doi.org/10.3390/ijms23010271 - 27 Dec 2021

Cited by 8 | Viewed by 2837

Abstract

The interleukin-21 receptor (IL-21R) can be upregulated in endothelial cells (EC) from ischemic muscles in mice following hind-limb ischemia (HLI), an experimental peripheral arterial disease (PAD) model, blocking this ligand–receptor pathway-impaired STAT3 activation, angiogenesis, and perfusion recovery. We sought to identify mRNA and microRNA transcripts that were differentially regulated following HLI, based on the ischemic muscle having intact, or reduced, IL-21/IL21R signaling. In this comparison, 200 mRNAs were differentially expressed but only six microRNA (miR)/miR clusters (and among these only miR-30b) were upregulated in EC isolated from ischemic muscle. Next, myoglobin-overexpressing transgenic (MgTG) C57BL/6 mice examined following HLI and IL-21 overexpression displayed greater angiogenesis, better perfusion recovery, and less tissue necrosis, with increased miR-30b expression. In EC cultured under hypoxia serum starvation, knock-down of miR-30b reduced, while overexpression of miR-30b increased IL-21-mediated EC survival and angiogenesis. In Il21r^−/− mice following HLI, miR-30b overexpression vs. control improved perfusion recovery, with a reduction of suppressor of cytokine signaling 3, a miR-30b target and negative regulator of STAT3. Together, miR-30b appears both necessary and sufficient for IL21/IL-21R-mediated angiogenesis and may present a new therapeutic option to treat PAD if the IL21R is not available for activation. Full article

(This article belongs to the Special Issue Arteriogenesis, Angiogenesis and Vascular Remodeling)

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Review

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20 pages, 4378 KiB

Open AccessReview

Building a Scaffold for Arteriovenous Fistula Maturation: Unravelling the Role of the Extracellular Matrix

by Suzanne L. Laboyrie, Margreet R. de Vries, Roel Bijkerk and Joris I. Rotmans

Int. J. Mol. Sci. 2023, 24(13), 10825; https://doi.org/10.3390/ijms241310825 - 28 Jun 2023

Cited by 2 | Viewed by 1356

Abstract

Vascular access is the lifeline for patients receiving haemodialysis as kidney replacement therapy. As a surgically created arteriovenous fistula (AVF) provides a high-flow conduit suitable for cannulation, it remains the vascular access of choice. In order to use an AVF successfully, the luminal diameter and the vessel wall of the venous outflow tract have to increase. This process is referred to as AVF maturation. AVF non-maturation is an important limitation of AVFs that contributes to their poor primary patency rates. To date, there is no clear overview of the overall role of the extracellular matrix (ECM) in AVF maturation. The ECM is essential for vascular functioning, as it provides structural and mechanical strength and communicates with vascular cells to regulate their differentiation and proliferation. Thus, the ECM is involved in multiple processes that regulate AVF maturation, and it is essential to study its anatomy and vascular response to AVF surgery to define therapeutic targets to improve AVF maturation. In this review, we discuss the composition of both the arterial and venous ECM and its incorporation in the three vessel layers: the tunica intima, media, and adventitia. Furthermore, we examine the effect of chronic kidney failure on the vasculature, the timing of ECM remodelling post-AVF surgery, and current ECM interventions to improve AVF maturation. Lastly, the suitability of ECM interventions as a therapeutic target for AVF maturation will be discussed. Full article

(This article belongs to the Special Issue Arteriogenesis, Angiogenesis and Vascular Remodeling)

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15 pages, 2712 KiB

Open AccessReview

Small GTPases and Their Regulators: A Leading Road toward Blood Vessel Development in Zebrafish

by Ritesh Urade, Yan-Hui Chiu, Chien-Chih Chiu and Chang-Yi Wu

Int. J. Mol. Sci. 2022, 23(9), 4991; https://doi.org/10.3390/ijms23094991 - 30 Apr 2022

Cited by 3 | Viewed by 2116

Abstract

Members of the Ras superfamily have been found to perform several functions leading to the development of eukaryotes. These small GTPases are divided into five major subfamilies, and their regulators can “turn on” and “turn off” signals. Recent studies have shown that this superfamily of proteins has various roles in the process of vascular development, such as vasculogenesis and angiogenesis. Here, we discuss the role of these subfamilies in the development of the vascular system in zebrafish. Full article

(This article belongs to the Special Issue Arteriogenesis, Angiogenesis and Vascular Remodeling)

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13 pages, 14497 KiB

Open AccessReview

Interdependence of Angiogenesis and Arteriogenesis in Development and Disease

by Ferdinand le Noble and Christian Kupatt

Int. J. Mol. Sci. 2022, 23(7), 3879; https://doi.org/10.3390/ijms23073879 - 31 Mar 2022

Cited by 6 | Viewed by 2587

Abstract

The structure of arterial networks is optimized to allow efficient flow delivery to metabolically active tissues. Optimization of flow delivery is a continuous process involving synchronization of the structure and function of the microcirculation with the upstream arterial network. Risk factors for ischemic cardiovascular diseases, such as diabetes mellitus and hyperlipidemia, adversely affect endothelial function, induce capillary regression, and disrupt the micro- to macrocirculation cross-talk. We provide evidence showing that this loss of synchronization reduces arterial collateral network recruitment upon arterial stenosis, and the long-term clinical outcome of current revascularization strategies in these patient cohorts. We describe mechanisms and signals contributing to synchronized growth of micro- and macrocirculation in development and upon ischemic challenges in the adult organism and identify potential therapeutic targets. We conclude that a long-term successful revascularization strategy should aim at both removing obstructions in the proximal part of the arterial tree and restoring “bottom-up” vascular communication. Full article

(This article belongs to the Special Issue Arteriogenesis, Angiogenesis and Vascular Remodeling)

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