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Arteriogenesis and Therapeutic Angiogenesis

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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 (1 September 2021) | Viewed by 44115

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Special Issue Editors

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

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

Special Issue Information

Dear Colleagues,

This Special Issue will welcome original research articles and review papers on all molecular aspects of arteriogenesis and therapeutic angiogenesis. Potential topics include, but are not limited to, the following:

Genetic and Environmental Mechanisms Controlling Formation and Maintenance of the Native Collateral Circulation;
Arteriogenesis, Therapeutic Angiogenesis and Peripheral Arterial Disease;
The Formation of Collateral Arterial Networks: Insights from the Developing Embryo;
Notch Signaling in Arteries: From Embryonic Development to Postnatal Homeostasis and Growth;
Multiple Pathways Converge in the Development of a Collateral Circulation
(Arteriogenesis);
Fluid Shear Stress and its Pathways in Arteriogenesis;
Cell and Gene Therapy in Peripheral Arterial Disease;
Epigenetic Mechanisms and Arteriogenesis;
Non-Coding RNA in vascular remodeling during arteriogenesis and angiogenesis
Bone Marrow Derived Cells in Arteriogenesis;
Local and Sustained Drug Delivery in Arteriogenesis;
Collateral Artery Growth in Man, from Assessment to Stimulation;
Therapeutic angiogenesis, from Assessment to Stimulation

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

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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
Cell and Gene Therapy
Critical Limb Ischemia
Therapeutic angiogenesis
Collateral Circulation

Published Papers (13 papers)

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Editorial

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3 pages, 183 KiB

Open AccessEditorial

Arteriogenesis and Therapeutic Angiogenesis—An Update

by Elisabeth Deindl and Paul H. A. Quax

Int. J. Mol. Sci. 2021, 22(24), 13244; https://doi.org/10.3390/ijms222413244 - 09 Dec 2021

Cited by 1 | Viewed by 1688

Abstract

Vascular occlusive diseases such myocardial infarction, peripheral artery disease of the lower extremities, or stroke still represent a substantial health burden worldwide [...] Full article

(This article belongs to the Special Issue Arteriogenesis and Therapeutic Angiogenesis)

Research

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18 pages, 4936 KiB

Open AccessArticle

Cold-Inducible RNA-Binding Protein but Not Its Antisense lncRNA Is a Direct Negative Regulator of Angiogenesis In Vitro and In Vivo via Regulation of the 14q32 angiomiRs—microRNA-329-3p and microRNA-495-3p

by Eveline A. C. Goossens, Licheng Zhang, Margreet R. de Vries, J. Wouter Jukema, Paul H. A. Quax and A. Yaël Nossent

Int. J. Mol. Sci. 2021, 22(23), 12678; https://doi.org/10.3390/ijms222312678 - 24 Nov 2021

Cited by 5 | Viewed by 1921

Abstract

Inhibition of the 14q32 microRNAs, miR-329-3p and miR-495-3p, improves post-ischemic neovascularization. Cold-inducible RNA-binding protein (CIRBP) facilitates maturation of these microRNAs. We hypothesized that CIRBP deficiency improves post-ischemic angiogenesis via downregulation of 14q32 microRNA expression. We investigated these regulatory mechanisms both in vitro and in vivo. We induced hindlimb ischemia in Cirp^−/− and C57Bl/6-J mice, monitored blood flow recovery with laser Doppler perfusion imaging, and assessed neovascularization via immunohistochemistry. Post-ischemic angiogenesis was enhanced in Cirp^−/− mice by 34.3% with no effects on arteriogenesis. In vivo at day 7, miR-329-3p and miR-495-3p expression were downregulated in Cirp^−/− mice by 40.6% and 36.2%. In HUVECs, CIRBP expression was upregulated under hypothermia, while miR-329-3p and miR-495-3p expression remained unaffected. siRNA-mediated CIRBP knockdown led to the downregulation of CIRBP-splice-variant-1 (CIRBP-SV1), CIRBP antisense long noncoding RNA (lncRNA-CIRBP-AS1), and miR-495-3p with no effects on the expression of CIRBP-SV2-4 or miR-329-3p. siRNA-mediated CIRBP knockdown improved HUVEC migration and tube formation. SiRNA-mediated lncRNA-CIRBP-AS1 knockdown had similar long-term effects. After short incubation times, however, only CIRBP knockdown affected angiogenesis, indicating that the effects of lncRNA-CIRBP-AS1 knockdown were secondary to CIRBP-SV1 downregulation. CIRBP is a negative regulator of angiogenesis in vitro and in vivo and acts, at least in part, through the regulation of miR-329-3p and miR-495-3p. Full article

(This article belongs to the Special Issue Arteriogenesis and Therapeutic Angiogenesis)

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16 pages, 4783 KiB

Open AccessArticle

Impact of C57BL/6J and SV-129 Mouse Strain Differences on Ischemia-Induced Postnatal Angiogenesis and the Associated Leukocyte Infiltration in a Murine Hindlimb Model of Ischemia

by Matthias Kübler, Philipp Götz, Anna Braumandl, Sebastian Beck, Hellen Ishikawa-Ankerhold and Elisabeth Deindl

Int. J. Mol. Sci. 2021, 22(21), 11795; https://doi.org/10.3390/ijms222111795 - 30 Oct 2021

Cited by 4 | Viewed by 2336

Abstract

Strain-related differences in arteriogenesis in inbred mouse strains have already been studied excessively. However, these analyses missed evaluating the mouse strain-related differences in ischemia-induced angiogenic capacities. With the present study, we wanted to shed light on the different angiogenic potentials and the associated leukocyte infiltration of C57BL/6J and SV-129 mice to facilitate the comparison of angiogenesis-related analyses between these strains. For the induction of angiogenesis, we ligated the femoral artery in 8–12-week-old male C57BL/6J and SV-129 mice and performed (immuno-) histological analyses on the ischemic gastrocnemius muscles collected 24 h or 7 days after ligation. As evidenced by hematoxylin and eosin staining, C57BL/6J mice showed reduced tissue damage but displayed an increased capillary-to-muscle fiber ratio and an elevated number of proliferating capillaries (CD31⁺/BrdU⁺ cells) compared to SV-129 mice, thus showing improved angiogenesis. Regarding the associated leukocyte infiltration, we found increased numbers of neutrophils (MPO⁺ cells), NETs (MPO⁺/CitH3⁺/DAPI⁺), and macrophages (CD68⁺ cells) in SV-129 mice, whereas macrophage polarization (MRC1^- vs. MRC1⁺) and total leukocyte infiltration (CD45⁺ cells) did not differ between the mouse strains. In summary, we show increased ischemia-induced angiogenic capacities in C57BL/6J mice compared to SV-129 mice, with the latter showing aggravated tissue damage, inflammation, and impaired angiogenesis. Full article

(This article belongs to the Special Issue Arteriogenesis and Therapeutic Angiogenesis)

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21 pages, 10064 KiB

Open AccessArticle

The Absence of Extracellular Cold-Inducible RNA-Binding Protein (eCIRP) Promotes Pro-Angiogenic Microenvironmental Conditions and Angiogenesis in Muscle Tissue Ischemia

by Matthias Kübler, Sebastian Beck, Lisa Lilian Peffenköver, Philipp Götz, Hellen Ishikawa-Ankerhold, Klaus T. Preissner, Silvia Fischer, Manuel Lasch and Elisabeth Deindl

Int. J. Mol. Sci. 2021, 22(17), 9484; https://doi.org/10.3390/ijms22179484 - 31 Aug 2021

Cited by 7 | Viewed by 2624

Abstract

Extracellular Cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern, is released from cells upon hypoxia and cold-stress. The overall absence of extra- and intracellular CIRP is associated with increased angiogenesis, most likely induced through influencing leukocyte accumulation. The aim of the present study was to specifically characterize the role of eCIRP in ischemia-induced angiogenesis together with the associated leukocyte recruitment. For analyzing eCIRPs impact, we induced muscle ischemia via femoral artery ligation (FAL) in mice in the presence or absence of an anti-CIRP antibody and isolated the gastrocnemius muscle for immunohistological analyses. Upon eCIRP-depletion, mice showed increased capillary/muscle fiber ratio and numbers of proliferating endothelial cells (CD31⁺/CD45⁻/BrdU⁺). This was accompanied by a reduction of total leukocyte count (CD45⁺), neutrophils (MPO⁺), neutrophil extracellular traps (NETs) (MPO⁺CitH3⁺), apoptotic area (ascertained via TUNEL assay), and pro-inflammatory M1-like polarized macrophages (CD68⁺/MRC1⁻) in ischemic muscle tissue. Conversely, the number of regenerative M2-like polarized macrophages (CD68⁺/MRC1⁺) was elevated. Altogether, we observed that eCIRP depletion similarly affected angiogenesis and leukocyte recruitment as described for the overall absence of CIRP. Thus, we propose that eCIRP is mainly responsible for modulating angiogenesis via promoting pro-angiogenic microenvironmental conditions in muscle ischemia. Full article

(This article belongs to the Special Issue Arteriogenesis and Therapeutic Angiogenesis)

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12 pages, 2460 KiB

Open AccessArticle

In Vivo Matrigel Plug Assay as a Potent Method to Investigate Specific Individual Contribution of Angiogenesis to Blood Flow Recovery in Mice

by Zeen Aref and Paul H. A. Quax

Int. J. Mol. Sci. 2021, 22(16), 8909; https://doi.org/10.3390/ijms22168909 - 18 Aug 2021

Cited by 3 | Viewed by 3360

Abstract

Neovascularization restores blood flow recovery after ischemia in peripheral arterial disease. The main two components of neovascularization are angiogenesis and arteriogenesis. Both of these processes contribute to functional improvements of blood flow after occlusion. However, discriminating between the specific contribution of each process is difficult. A frequently used model for investigating neovascularization is the murine hind limb ischemia model (HLI). With this model, it is difficult to determine the role of angiogenesis, because usually the timing for the sacrifice of the mice is chosen to be optimal for the analysis of arteriogenesis. More importantly, the occurring angiogenesis in the distal calf muscles is probably affected by the proximally occurring arteriogenesis. Therefore, to understand and subsequently intervene in the process of angiogenesis, a model is needed which investigates angiogenesis without the influence of arteriogenesis. In this study we evaluated the in vivo Matrigel plug assay in genetic deficient mice to investigate angiogenesis. Mice deficient for interferon regulatory factor (IRF)3, IRF7, RadioProtective 105 (RP105), Chemokine CC receptor CCR7, and p300/CBP-associated factor (PCAF) underwent the in vivo Matrigel model. Histological analysis of the Matrigel plugs showed an increased angiogenesis in mice deficient of IRF3, IRF7, and RP105, and a decreased angiogenesis in PCAF deficient mice. Our results also suggest an involvement of CCR7 in angiogenesis. Comparing our results with results of the HLI model found in the literature suggests that the in vivo Matrigel plug assay is superior in evaluating the angiogenic response after ischemia. Full article

(This article belongs to the Special Issue Arteriogenesis and Therapeutic Angiogenesis)

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16 pages, 23223 KiB

Open AccessArticle

Proangiogenic Effect of 2A-Peptide Based Multicistronic Recombinant Constructs Encoding VEGF and FGF2 Growth Factors

by Dilara Z. Gatina, Ekaterina E. Garanina, Margarita N. Zhuravleva, Gulnaz E. Synbulatova, Adelya F. Mullakhmetova, Valeriya V. Solovyeva, Andrey P. Kiyasov, Catrin S. Rutland, Albert A. Rizvanov and Ilnur I. Salafutdinov

Int. J. Mol. Sci. 2021, 22(11), 5922; https://doi.org/10.3390/ijms22115922 - 31 May 2021

Cited by 6 | Viewed by 3713

Abstract

Coronary artery disease remains one of the primary healthcare problems due to the high cost of treatment, increased number of patients, poor clinical outcomes, and lack of effective therapy. Though pharmacological and surgical treatments positively affect symptoms and arrest the disease progression, they generally exhibit a limited effect on the disease outcome. The development of alternative therapeutic approaches towards ischemic disease treatment, especially of decompensated forms, is therefore relevant. Therapeutic angiogenesis, stimulated by various cytokines, chemokines, and growth factors, provides the possibility of restoring functional blood flow in ischemic tissues, thereby ensuring the regeneration of the damaged area. In the current study, based on the clinically approved plasmid vector pVax1, multigenic constructs were developed encoding vascular endothelial growth factor (VEGF), fibroblast growth factors (FGF2), and the DsRed fluorescent protein, integrated via picornaviruses’ furin-2A peptide sequences. In vitro experiments demonstrated that genetically modified cells with engineered plasmid constructs expressed the target proteins. Overexpression of VEGF and FGF2 resulted in increased levels of the recombinant proteins. Concomitantly, these did not lead to a significant shift in the general secretory profile of modified HEK293T cells. Simultaneously, the secretome of genetically modified cells showed significant stimulating effects on the formation of capillary-like structures by HUVEC (endothelial cells) in vitro. Our results revealed that when the multicistronic multigene vectors encoding 2A peptide sequences are created, transient transgene co-expression is ensured. The results obtained indicated the mutual synergistic effects of the growth factors VEGF and FGF2 on the proliferation of endothelial cells in vitro. Thus, recombinant multicistronic multigenic constructs might serve as a promising approach for establishing safe and effective systems to treat ischemic diseases. Full article

(This article belongs to the Special Issue Arteriogenesis and Therapeutic Angiogenesis)

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18 pages, 4844 KiB

Open AccessArticle

BMP Receptor Inhibition Enhances Tissue Repair in Endoglin Heterozygous Mice

by Wineke Bakker, Calinda K. E. Dingenouts, Kirsten Lodder, Karien C. Wiesmeijer, Alwin de Jong, Kondababu Kurakula, Hans-Jurgen J. Mager, Anke M. Smits, Margreet R. de Vries, Paul H. A. Quax and Marie José T. H. Goumans

Int. J. Mol. Sci. 2021, 22(4), 2010; https://doi.org/10.3390/ijms22042010 - 18 Feb 2021

Cited by 3 | Viewed by 2048

Abstract

Hereditary hemorrhagic telangiectasia type 1 (HHT1) is a severe vascular disorder caused by mutations in the TGFβ/BMP co-receptor endoglin. Endoglin haploinsufficiency results in vascular malformations and impaired neoangiogenesis. Furthermore, HHT1 patients display an impaired immune response. To date it is not fully understood how endoglin haploinsufficient immune cells contribute to HHT1 pathology. Therefore, we investigated the immune response during tissue repair in Eng+/− mice, a model for HHT1. Eng+/− mice exhibited prolonged infiltration of macrophages after experimentally induced myocardial infarction. Moreover, there was an increased number of inflammatory M1-like macrophages (Ly6C^high/CD206⁻) at the expense of reparative M2-like macrophages (Ly6C^low/CD206⁺). Interestingly, HHT1 patients also showed an increased number of inflammatory macrophages. In vitro analysis revealed that TGFβ-induced differentiation of Eng+/− monocytes into M2-like macrophages was blunted. Inhibiting BMP signaling by treating monocytes with LDN-193189 normalized their differentiation. Finally, LDN treatment improved heart function after MI and enhanced vascularization in both wild type and Eng+/− mice. The beneficial effect of LDN was also observed in the hind limb ischemia model. While blood flow recovery was hampered in vehicle-treated animals, LDN treatment improved tissue perfusion recovery in Eng+/− mice. In conclusion, BMPR kinase inhibition restored HHT1 macrophage imbalance in vitro and improved tissue repair after ischemic injury in Eng+/− mice. Full article

(This article belongs to the Special Issue Arteriogenesis and Therapeutic Angiogenesis)

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14 pages, 7448 KiB

Open AccessArticle

Assessment of Microvessel Permeability in Murine Atherosclerotic Vein Grafts Using Two-Photon Intravital Microscopy

by Fabiana Baganha, Laila Ritsma, Paul H. A. Quax and Margreet R. de Vries

Int. J. Mol. Sci. 2020, 21(23), 9244; https://doi.org/10.3390/ijms21239244 - 03 Dec 2020

Cited by 5 | Viewed by 2966

Abstract

Plaque angiogenesis and plaque hemorrhage are major players in the destabilization and rupture of atherosclerotic lesions. As these are dynamic processes, imaging of plaque angiogenesis, especially the integrity or leakiness of angiogenic vessels, can be an extremely useful tool in the studies on atherosclerosis pathophysiology. Visualizing plaque microvessels in 3D would enable us to study the architecture and permeability of adventitial and intimal plaque microvessels in advanced atherosclerotic lesions. We hypothesized that a comparison of the vascular permeability between healthy continuous and fenestrated as well as diseased leaky microvessels, would allow us to evaluate plaque microvessel leakiness. We developed and validated a two photon intravital microscopy (2P-IVM) method to assess the leakiness of plaque microvessels in murine atherosclerosis-prone ApoE3*Leiden vein grafts based on the quantification of fluorescent-dextrans extravasation in real-time. We describe a novel 2P-IVM set up to study vessels in the neck region of living mice. We show that microvessels in vein graft lesions are in their pathological state more permeable in comparison with healthy continuous and fenestrated microvessels. This 2P-IVM method is a promising approach to assess plaque angiogenesis and leakiness. Moreover, this method is an important advancement to validate therapeutic angiogenic interventions in preclinical atherosclerosis models. Full article

(This article belongs to the Special Issue Arteriogenesis and Therapeutic Angiogenesis)

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Review

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Role of Vascular Smooth Muscle Cell Phenotype Switching in Arteriogenesis

by Jasni Viralippurath Ashraf and Ayman Al Haj Zen

Int. J. Mol. Sci. 2021, 22(19), 10585; https://doi.org/10.3390/ijms221910585 - 30 Sep 2021

Cited by 27 | Viewed by 4496

Abstract

Arteriogenesis is one of the primary physiological means by which the circulatory collateral system restores blood flow after significant arterial occlusion in peripheral arterial disease patients. Vascular smooth muscle cells (VSMCs) are the predominant cell type in collateral arteries and respond to altered blood flow and inflammatory conditions after an arterial occlusion by switching their phenotype between quiescent contractile and proliferative synthetic states. Maintaining the contractile state of VSMC is required for collateral vascular function to regulate blood vessel tone and blood flow during arteriogenesis, whereas synthetic SMCs are crucial in the growth and remodeling of the collateral media layer to establish more stable conduit arteries. Timely VSMC phenotype switching requires a set of coordinated actions of molecular and cellular mediators to result in an expansive remodeling of collaterals that restores the blood flow effectively into downstream ischemic tissues. This review overviews the role of VSMC phenotypic switching in the physiological arteriogenesis process and how the VSMC phenotype is affected by the primary triggers of arteriogenesis such as blood flow hemodynamic forces and inflammation. Better understanding the role of VSMC phenotype switching during arteriogenesis can identify novel therapeutic strategies to enhance revascularization in peripheral arterial disease. Full article

(This article belongs to the Special Issue Arteriogenesis and Therapeutic Angiogenesis)

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16 pages, 2568 KiB

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Clinical Application of Novel Therapies for Coronary Angiogenesis: Overview, Challenges, and Prospects

by Mohamed Sabra, Catherine Karbasiafshar, Ahmed Aboulgheit, Sidharth Raj, M. Ruhul Abid and Frank W. Sellke

Int. J. Mol. Sci. 2021, 22(7), 3722; https://doi.org/10.3390/ijms22073722 - 02 Apr 2021

Cited by 19 | Viewed by 2730

Abstract

Cardiovascular diseases continue to be the leading cause of death worldwide, with ischemic heart disease as the most significant contributor. Pharmacological and surgical interventions have improved clinical outcomes, but are unable to ameliorate advanced stages of end-heart failure. Successful preclinical studies of new therapeutic modalities aimed at revascularization have shown short lasting to no effects in the clinical practice. This lack of success may be attributed to current challenges in patient selection, endpoint measurements, comorbidities, and delivery systems. Although challenges remain, the field of therapeutic angiogenesis is evolving, as novel strategies and bioengineering approaches emerge to optimize delivery and efficacy. Here, we describe the structure, vascularization, and regulation of the vascular system with particular attention to the endothelium. We proceed to discuss preclinical and clinical findings and present challenges and future prospects in the field. Full article

(This article belongs to the Special Issue Arteriogenesis and Therapeutic Angiogenesis)

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23 pages, 1155 KiB

Open AccessReview

The Role of Circulating Biomarkers in Peripheral Arterial Disease

by Goren Saenz-Pipaon, Esther Martinez-Aguilar, Josune Orbe, Arantxa González Miqueo, Leopoldo Fernandez-Alonso, Jose Antonio Paramo and Carmen Roncal

Int. J. Mol. Sci. 2021, 22(7), 3601; https://doi.org/10.3390/ijms22073601 - 30 Mar 2021

Cited by 38 | Viewed by 5738

Abstract

Peripheral arterial disease (PAD) of the lower extremities is a chronic illness predominantly of atherosclerotic aetiology, associated to traditional cardiovascular (CV) risk factors. It is one of the most prevalent CV conditions worldwide in subjects >65 years, estimated to increase greatly with the aging of the population, becoming a severe socioeconomic problem in the future. The narrowing and thrombotic occlusion of the lower limb arteries impairs the walking function as the disease progresses, increasing the risk of CV events (myocardial infarction and stroke), amputation and death. Despite its poor prognosis, PAD patients are scarcely identified until the disease is advanced, highlighting the need for reliable biomarkers for PAD patient stratification, that might also contribute to define more personalized medical treatments. In this review, we will discuss the usefulness of inflammatory molecules, matrix metalloproteinases (MMPs), and cardiac damage markers, as well as novel components of the liquid biopsy, extracellular vesicles (EVs), and non-coding RNAs for lower limb PAD identification, stratification, and outcome assessment. We will also explore the potential of machine learning methods to build prediction models to refine PAD assessment. In this line, the usefulness of multimarker approaches to evaluate this complex multifactorial disease will be also discussed. Full article

(This article belongs to the Special Issue Arteriogenesis and Therapeutic Angiogenesis)

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13 pages, 1193 KiB

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Emerging Role of AP-1 Transcription Factor JunB in Angiogenesis and Vascular Development

by Yasuo Yoshitomi, Takayuki Ikeda, Hidehito Saito-Takatsuji and Hideto Yonekura

Int. J. Mol. Sci. 2021, 22(6), 2804; https://doi.org/10.3390/ijms22062804 - 10 Mar 2021

Cited by 27 | Viewed by 4049

Abstract

Blood vessels are essential for the formation and maintenance of almost all functional tissues. They play fundamental roles in the supply of oxygen and nutrition, as well as development and morphogenesis. Vascular endothelial cells are the main factor in blood vessel formation. Recently, research findings showed heterogeneity in vascular endothelial cells in different tissue/organs. Endothelial cells alter their gene expressions depending on their cell fate or angiogenic states of vascular development in normal and pathological processes. Studies on gene regulation in endothelial cells demonstrated that the activator protein 1 (AP-1) transcription factors are implicated in angiogenesis and vascular development. In particular, it has been revealed that JunB (a member of the AP-1 transcription factor family) is transiently induced in endothelial cells at the angiogenic frontier and controls them on tip cells specification during vascular development. Moreover, JunB plays a role in tissue-specific vascular maturation processes during neurovascular interaction in mouse embryonic skin and retina vasculatures. Thus, JunB appears to be a new angiogenic factor that induces endothelial cell migration and sprouting particularly in neurovascular interaction during vascular development. In this review, we discuss the recently identified role of JunB in endothelial cells and blood vessel formation. Full article

(This article belongs to the Special Issue Arteriogenesis and Therapeutic Angiogenesis)

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27 pages, 16595 KiB

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Current Status of Angiogenic Cell Therapy and Related Strategies Applied in Critical Limb Ischemia

by Lucía Beltrán-Camacho, Marta Rojas-Torres and Mᵃ Carmen Durán-Ruiz

Int. J. Mol. Sci. 2021, 22(5), 2335; https://doi.org/10.3390/ijms22052335 - 26 Feb 2021

Cited by 36 | Viewed by 4992

Abstract

Critical limb ischemia (CLI) constitutes the most severe form of peripheral arterial disease (PAD), it is characterized by progressive blockade of arterial vessels, commonly correlated to atherosclerosis. Currently, revascularization strategies (bypass grafting, angioplasty) remain the first option for CLI patients, although less than 45% of them are eligible for surgical intervention mainly due to associated comorbidities. Moreover, patients usually require amputation in the short-term. Angiogenic cell therapy has arisen as a promising alternative for these “no-option” patients, with many studies demonstrating the potential of stem cells to enhance revascularization by promoting vessel formation and blood flow recovery in ischemic tissues. Herein, we provide an overview of studies focused on the use of angiogenic cell therapies in CLI in the last years, from approaches testing different cell types in animal/pre-clinical models of CLI, to the clinical trials currently under evaluation. Furthermore, recent alternatives related to stem cell therapies such as the use of secretomes, exosomes, or even microRNA, will be also described. Full article

(This article belongs to the Special Issue Arteriogenesis and Therapeutic Angiogenesis)

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