Decoding the Complexity of Angiogenesis: Insights into Vascular Formation and Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Cardiovascular System".

Deadline for manuscript submissions: 29 January 2027 | Viewed by 8692

Editor

Special Issue Information

Dear Colleagues,

Angiogenesis, in the strictest sense, is defined as the physiological process of vessel formation from the pre-existing vasculature. However, it is important to note that angiogenesis and vasculogenesis occur during embryonic development and in physiological and pathophysiological conditions. Angiogenesis is a fascinating fundamental biological process involving the interplay of different cell types and signaling molecules, and it is an extremely relevant therapeutic target under multiple disease conditions. The present Special Issue of Cells, entitled “Decoding the Complexity of Angiogenesis: Insights into Vascular Formation and Disease”, aims to publish high-quality original research and reviews dealing with this fascinating topic.

Key themes that will be explored within this Special Issue include mechanistic insights into cell–cell interactions, molecular downstream mechanisms, pathophysiologically relevant models, and mechanisms of developmental angiogenesis. Furthermore, translational approaches relevant to diseases with modified angiogenesis are highly appropriate.

Prof. Dr. Kay-Dietrich Wagner
Guest Editor

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Keywords

  • angiogenesis
  • vasculogenesis
  • development
  • physiological angiogenesis
  • pathophysiology
  • cell–cell communication
  • cell signaling

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Published Papers (6 papers)

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Research

Jump to: Review

20 pages, 19231 KB  
Article
B Cell Deficiency Impairs Collateral Artery Growth by Influencing Early and Late Regenerative Inflammation
by Matthias Kübler, Amanda Geml, Katharina Elbs, Franziska Heim, Kira-Sofie Wimmer, Carolin Baur, Daphne Merkus and Elisabeth Deindl
Cells 2026, 15(15), 1372; https://doi.org/10.3390/cells15151372 - 29 Jul 2026
Viewed by 282
Abstract
Arteriogenesis, the growth of pre-existing collateral arteries in response to arterial occlusion, is critically regulated by perivascular immune cells. While innate immune contributions are well-established, the role of B lymphocytes remains poorly understood. We investigated the impact of B cell deficiency on arteriogenesis [...] Read more.
Arteriogenesis, the growth of pre-existing collateral arteries in response to arterial occlusion, is critically regulated by perivascular immune cells. While innate immune contributions are well-established, the role of B lymphocytes remains poorly understood. We investigated the impact of B cell deficiency on arteriogenesis using B cell-deficient JHT mice in a murine hindlimb model of femoral artery ligation (FAL). Laser-Doppler perfusion imaging, immunofluorescence staining, Giemsa staining, flow cytometry, and differential blood counts were performed at defined time points after FAL. B cell-deficient mice exhibited significantly impaired perfusion recovery on days 3 and 7 post-FAL, accompanied by reduced collateral artery diameter growth and diminished vascular cell proliferation. Early immune analysis revealed elevated platelet–neutrophil aggregate (PNA) formation and increased perivascular mast cell degranulation in B cell-deficient mice despite unchanged circulating cell counts. On day 7, perivascular M2-like macrophage numbers were selectively reduced. Furthermore, B cell deficiency disrupted the temporal reprogramming of γδ T cell subsets, impairing the shift from pro-inflammatory IFN-γ-associated to anti-inflammatory IL-10-associated subpopulations. These findings demonstrate for the first time that B cells are essential coordinators of the sequential innate and regenerative immune response driving productive collateral artery growth, positioning them as potential targets for therapeutic arteriogenesis strategies. Full article
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25 pages, 23037 KB  
Article
Small Subset, Big Impact: Regulatory Function of γδ T Cells in Arteriogenesis
by Kira-Sofie Wimmer, Carolin Baur, Matthias Kübler, Christoph Arnholdt, Konda Kumaraswami, Franziska Heim, Katharina Elbs, Michael Reha Rohrmoser, Daphne Merkus and Elisabeth Deindl
Cells 2026, 15(8), 709; https://doi.org/10.3390/cells15080709 - 17 Apr 2026
Cited by 1 | Viewed by 971
Abstract
Despite the identification of several mediators of arteriogenesis, the growth of natural bypass, the role of lymphocytes, particularly T cells, in this process remains poorly defined. Among these, γδ T cells, which express alternative T cell receptors, have emerged as a key immune [...] Read more.
Despite the identification of several mediators of arteriogenesis, the growth of natural bypass, the role of lymphocytes, particularly T cells, in this process remains poorly defined. Among these, γδ T cells, which express alternative T cell receptors, have emerged as a key immune component. This study examined the roles of αβ and γδ T cells in arteriogenesis using a murine hindlimb model. While the absence of αβ T cells did not affect arteriogenesis, γδ T cell depletion markedly reduced vascular cell proliferation and perfusion recovery. Early phase analyses revealed impaired mast cell activation, whereas platelet–neutrophil aggregates and neutrophil extravasation were unaffected. In the later proliferative phase, γδ T cell depletion hindered perivascular M2-like (MRC1+) macrophage accumulation. Flow cytometric analysis of whole blood in wildtype mice revealed a temporal shift in γδ T cell populations from a CD27+/CD39 phenotype, commonly associated with pro-inflammatory functions and IFNγ production, to CD39+ phenotypes, which have been linked to anti-inflammatory properties and IL-10 production. In rescue experiments, administration of IFNγ to γδ T cell-depleted mice restored mast cell activation, whereas IL-10 treatment reestablished M2-like (MRC1+) macrophage accumulation. These findings collectively identify γδ T cells as critical regulators of both early and late phases of arteriogenesis through coordinated inflammatory and regenerative mechanisms. Full article
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17 pages, 6355 KB  
Article
Regulation of Hindbrain Vascular Development by rps20 in Zebrafish
by Xinyu Shen, Zhaozhi Wen, Shunze Deng, Yuxuan Qiu, Weijie Ma, Xinyue Dong, Jie Gong, Yu Zhang, Dong Liu and Bing Xu
Cells 2025, 14(14), 1070; https://doi.org/10.3390/cells14141070 - 13 Jul 2025
Cited by 1 | Viewed by 2014
Abstract
During aging, the brain vasculature undergoes significant deterioration characterized by increased arterial tortuosity, compromised blood–brain barrier integrity, and reduced cerebral blood flow, all of which contribute to various neurological disorders. Thus, understanding the mechanisms underlying aging-related cerebrovascular defects is critical for developing strategies [...] Read more.
During aging, the brain vasculature undergoes significant deterioration characterized by increased arterial tortuosity, compromised blood–brain barrier integrity, and reduced cerebral blood flow, all of which contribute to various neurological disorders. Thus, understanding the mechanisms underlying aging-related cerebrovascular defects is critical for developing strategies to alleviate aging-associated neurological diseases. In this study, we investigated the role of aging-related genes in brain vascular development using zebrafish as an in vivo model. By thoroughly analyzing scRNA-seq datasets of mid- and old-aged brain vascular endothelial cells (human/mouse), we found ribosomal protein S20 (rps20) significantly down-regulated during aging. qPCR analysis and whole-mount in situ hybridization validated a high expression of rps20 during early zebrafish development, which progressively decreased in adult and aged zebrafish brains. Functional studies using the CRISPR/Cas9-mediated knockout of rps20 revealed an impaired growth of central arteries in the hindbrain and a marked increased intracranial hemorrhage incidence. Mechanistically, qPCR analysis demonstrated a significant downregulation of vegfa, cxcl12b, and cxcr4a, key signaling molecules required for hindbrain vascular development, in rps20-deficient embryos. In conclusion, our findings demonstrate that rps20 is essential for proper brain vascular development and the maintenance of vascular homeostasis in zebrafish, revealing a novel mechanism by which aging-related genes regulate brain vascular development. This study provides new insights that may aid in understanding and treating aging-associated vascular malformations and neurological pathologies. Full article
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Review

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35 pages, 1636 KB  
Review
Rewiring Tumor Lifelines: Translating Hypoxia- and Pseudohypoxia-Driven Angiogenesis into Therapeutic Breakthroughs
by Michael Boulis, Fady Tawfik and Anitha Kota Shenoy
Cells 2026, 15(14), 1295; https://doi.org/10.3390/cells15141295 - 20 Jul 2026
Viewed by 476
Abstract
Hypoxia and the evolving concept of pseudohypoxia are critical in driving tumor angiogenesis, contributing to malignancy progression and therapeutic resistance. Angiogenesis, a common feature of many solid tumors, is promoted by hypoxia-induced overexpression of pro-angiogenic factors (e.g., VEGF, FGF) and genetic mutations (e.g., [...] Read more.
Hypoxia and the evolving concept of pseudohypoxia are critical in driving tumor angiogenesis, contributing to malignancy progression and therapeutic resistance. Angiogenesis, a common feature of many solid tumors, is promoted by hypoxia-induced overexpression of pro-angiogenic factors (e.g., VEGF, FGF) and genetic mutations (e.g., VHL, SDH) that stabilize hypoxia-inducible factors (HIF) even in normal oxygen conditions, a phenomenon known as pseudohypoxia. Recent experimental studies challenge the view that hypoxia universally enhances vessel growth. In certain models, severe oxygen deprivation impairs angiogenesis. Furthermore, tumor-mediated metabolic reprogramming can drive immune evasion via HIF stabilization in immune cells. These paradoxes, together with persistent therapy resistance and the limited effectiveness of current anti-angiogenic treatments, reveal critical gaps in our understanding of how hypoxic signaling modulates vascular and immune dynamics within the tumor microenvironment. These complexities demand more detailed exploration of underlying processes and the development of innovative therapeutic strategies. Here, we review recent mechanistic studies on tumor angiogenesis, summarizing therapeutic and diagnostic advances from both preclinical and clinical studies. We further discuss strategies to exploit hypoxic vulnerabilities, including HIF inhibitors, hypoxia-activated prodrugs, vascular normalization, combination regimens to restore immunity, biomarker-guided patient selection, and advanced hypoxia-targeted imaging to improve outcomes in angiogenesis-driven cancers. Full article
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18 pages, 319 KB  
Review
Role of Angiogenesis in Retinal Diseases and New Advances in Drug Development
by Emma Boey, Humza Zaidi, Tina Tang and Amirfarbod Yazdanyar
Cells 2025, 14(23), 1849; https://doi.org/10.3390/cells14231849 - 24 Nov 2025
Cited by 2 | Viewed by 2657
Abstract
Dysregulation of angiogenesis can cause a disruption in oxygen and nutrient delivery, resulting in impaired neural retinal function. Understanding the underlying components involved in its pathophysiology is essential to develop new treatments for preserving and restoring vision. The aim of this review is [...] Read more.
Dysregulation of angiogenesis can cause a disruption in oxygen and nutrient delivery, resulting in impaired neural retinal function. Understanding the underlying components involved in its pathophysiology is essential to develop new treatments for preserving and restoring vision. The aim of this review is to describe the role of angiogenesis in different retinal and choroidal pathologies and evaluate current and emerging anti-angiogenic therapies for retinopathies. Current research articles, focusing on the latest clinical trials from the last two decades, were used to write this review. We discuss normal angiogenesis, in contrast to pathological angiogenesis, in four diseases: retinal vein occlusion (RVO), age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinopathy of prematurity (ROP). Alongside these diseases, this review discusses relevant anti-angiogenic therapies that have been approved for use and are under active investigation through clinical trials for their safety and efficacy. Full article
10 pages, 526 KB  
Review
A Change of Hallmark: An Update
by Tom Donnem, David Kerr, Leonid L Nikitenko and Francesco Pezzella
Cells 2025, 14(19), 1490; https://doi.org/10.3390/cells14191490 - 24 Sep 2025
Viewed by 1283
Abstract
We review the latest development in non-angiogenic tumours. We focused on the last 3 years except the rarer tumours, for which the papers are older. Following the explanation of the modified hallmark of cancer, inducing angiogenesis and/or accessing vessels, the authors review primary [...] Read more.
We review the latest development in non-angiogenic tumours. We focused on the last 3 years except the rarer tumours, for which the papers are older. Following the explanation of the modified hallmark of cancer, inducing angiogenesis and/or accessing vessels, the authors review primary and metastatic tumours growing into lung, liver and brain, plus oral cancer, lymphomas and node metastasis. Also progress in treatment, not many unfortunately, and techniques in non-angiogenic tumours are discussed. Full article
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