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Role of Neuronal Guidance Cues in Inflammation and Vascular Biology
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Role of Neuronal Guidance Cues in Inflammation and Vascular Biology

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 28781

Special Issue Editor

Dr. Janine M. van Gils

E-Mail Website
Guest Editor
Leiden University Medical Center—LUMC, Leiden, The Netherlands
Interests: axonal guidance cues; endothelium; monocyte; macrophage; atherosclerosis; netrin; cell biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The observation that the anatomy and genetic expression patterns of the vascular system of vertebrates often overlap with the nervous system has led to one of the major recent insights in developmental vascular biology, i.e., that the coordinated patterning of nerves and vessels is achieved by each system separately using the same cues and signals. These conserved patterning factors, together known as neuronal guidance cues, were first identified in neural development and involve four major families of conserved ligands netrins, slits, semaphorins, and ephrins. More recently, their critical roles in physiological and pathological regulation of vascular biology and immune responses have been increasingly recognized. As has been shown by their roles in various vascular (patho)physiologies, such as atherosclerosis development and progression, endothelial (blood-brain) barrier, retinopathy, and tumor angiogenesis.

The scope of this Special Issue covers the various roles of neuronal guidance cues in inflammation and vascular biology. We welcome contributions of original research articles, as well as review articles, that further unravel the role of neuronal guidance molecules in inflammation and vascular biology. We encourage the submission of papers approaching the topic from different points of view and different levels, from both micro- and microvasculature as well as lymphatic vasculature, and from basic molecular mechanisms and to translational approaches. Different approaches can extend our knowledge of neuronal guidance molecules can contribute to future therapeutic strategies aim to preserve and improve vascular health.

Dr. Janine van Gils
Guest Editor

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.

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Published Papers (7 papers)

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Research

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15 pages, 1001 KiB  
Article
Brain-Derived Neurotrophic Factor during Oral Glucose Tolerance Test Predicts Cardiovascular Outcomes
by I-Te Lee, Yu-Hsuan Li and Wayne Huey-Herng Sheu
Int. J. Mol. Sci. 2020, 21(14), 5008; https://doi.org/10.3390/ijms21145008 - 15 Jul 2020
Cited by 8 | Viewed by 1924
Abstract
We investigated if brain-derived neurotrophic factor (BDNF) accumulation after glucose intake could predict cardiovascular outcomes. We enrolled patients admitted for angiography due to angina. After their conditions stabilized, serum BDNF levels were detected at 0, 30, and 120 min during oral glucose tolerance [...] Read more.
We investigated if brain-derived neurotrophic factor (BDNF) accumulation after glucose intake could predict cardiovascular outcomes. We enrolled patients admitted for angiography due to angina. After their conditions stabilized, serum BDNF levels were detected at 0, 30, and 120 min during oral glucose tolerance test (OGTT). Area under the curve (AUC) of BDNF was calculated. The first occurrence of nonfatal myocardial infarction, nonfatal stroke, and all-cause mortality served as the primary composite endpoint. Of 480 enrolled patients, 428 completed the follow-up, and 36 primary endpoint events occurred during a median follow-up of 4.4 years. The area under the receiver operating characteristic curve significantly increased from 0.61 (95% confidence interval (CI): 0.52–0.73) for the Framingham risk score (FRS) alone model to 0.72 (95%CI: 0.63–0.81) for the AUC of BDNF plus FRS model (p = 0.016) for predicting the primary endpoint, but not to 0.65 (95%CI: 0.55–0.75) for the fasting BDNF plus FRS model (p = 0.160). Grouped by median AUC of BDNF of 38.0 (ng/mL) × h, the low BDNF group had a significantly higher risk of the endpoint than the high BDNF group (hazard ratio = 3.410, 95%CI: 1.520–7.653, p = 0.003). In conclusion, AUC of BDNF during OGTT could be superior to fasting BDNF for predicting a low cardiovascular risk. Full article
(This article belongs to the Special Issue Role of Neuronal Guidance Cues in Inflammation and Vascular Biology)
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16 pages, 3586 KiB  
Article
Endothelial Semaphorin 3F Maintains Endothelial Barrier Function and Inhibits Monocyte Migration
by Huayu Zhang, Dianne Vreeken, Abidemi Junaid, Gangqi Wang, Wendy M. P. J. Sol, Ruben G. de Bruin, Anton Jan van Zonneveld and Janine M. van Gils
Int. J. Mol. Sci. 2020, 21(4), 1471; https://doi.org/10.3390/ijms21041471 - 21 Feb 2020
Cited by 9 | Viewed by 3288
Abstract
In normal physiology, endothelial cells (ECs) form a vital barrier between the blood and underlying tissue controlling leukocyte diapedesis and vascular inflammation. Emerging data suggest that neuronal guidance cues, typically expressed during development, have roles outside the nervous system in vascular biology and [...] Read more.
In normal physiology, endothelial cells (ECs) form a vital barrier between the blood and underlying tissue controlling leukocyte diapedesis and vascular inflammation. Emerging data suggest that neuronal guidance cues, typically expressed during development, have roles outside the nervous system in vascular biology and immune responses. In particular, Class III semaphorins have been reported to affect EC migration and angiogenesis. While ECs express high levels of semaphorin 3F (SEMA3F), little is known about its function in mature ECs. Here we show that SEMA3F expression is reduced by inflammatory stimuli and increased by laminar flow. Endothelial cells exposed to laminar flow secrete SEMA3F, which subsequently binds to heparan sulfates on the surface of ECs. However, under pro-inflammatory conditions, reduced levels of SEMA3F make ECs more prone to monocyte diapedesis and display impaired barrier function as measured with an electric cell–substrate impedance sensing system and a microfluidic system. In addition, we demonstrate that SEMA3F can directly inhibit the migration of activated monocytes. Taken together, our data suggest an important homeostatic function for EC-expressed SEMA3F, serving as a mediator of endothelial quiescence. Full article
(This article belongs to the Special Issue Role of Neuronal Guidance Cues in Inflammation and Vascular Biology)
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Review

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24 pages, 7340 KiB  
Review
Netrin-1: A Modulator of Macrophage Driven Acute and Chronic Inflammation
by Laura Ziegon and Martin Schlegel
Int. J. Mol. Sci. 2022, 23(1), 275; https://doi.org/10.3390/ijms23010275 - 27 Dec 2021
Cited by 14 | Viewed by 4580
Abstract
Netrins belong to the family of laminin-like secreted proteins, which guide axonal migration and neuronal growth in the developing central nervous system. Over the last 20 years, it has been established that netrin-1 acts as a chemoattractive or chemorepulsive cue in diverse biological [...] Read more.
Netrins belong to the family of laminin-like secreted proteins, which guide axonal migration and neuronal growth in the developing central nervous system. Over the last 20 years, it has been established that netrin-1 acts as a chemoattractive or chemorepulsive cue in diverse biological processes far beyond neuronal development. Netrin-1 has been shown to play a central role in cell adhesion, cell migration, proliferation, and cell survival in neuronal and non-neuronal tissue. In this context, netrin-1 was found to orchestrate organogenesis, angiogenesis, tumorigenesis, and inflammation. In inflammation, as in neuronal development, netrin-1 plays a dichotomous role directing the migration of leukocytes, especially monocytes in the inflamed tissue. Monocyte-derived macrophages have long been known for a similar dual role in inflammation. In response to pathogen-induced acute injury, monocytes are rapidly recruited to damaged tissue as the first line of immune defense to phagocyte pathogens, present antigens to initiate the adaptive immune response, and promote wound healing in the resolution phase. On the other hand, dysregulated macrophages with impaired phagocytosis and egress capacity accumulate in chronic inflammation sites and foster the maintenance—and even the progression—of chronic inflammation. In this review article, we will highlight the dichotomous roles of netrin-1 and its impact on acute and chronic inflammation. Full article
(This article belongs to the Special Issue Role of Neuronal Guidance Cues in Inflammation and Vascular Biology)
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32 pages, 2286 KiB  
Review
Unraveling Axon Guidance during Axotomy and Regeneration
by Miguel E. Domínguez-Romero and Paula G. Slater
Int. J. Mol. Sci. 2021, 22(15), 8344; https://doi.org/10.3390/ijms22158344 - 03 Aug 2021
Cited by 14 | Viewed by 5572
Abstract
During neuronal development and regeneration axons extend a cytoskeletal-rich structure known as the growth cone, which detects and integrates signals to reach its final destination. The guidance cues “signals” bind their receptors, activating signaling cascades that result in the regulation of the growth [...] Read more.
During neuronal development and regeneration axons extend a cytoskeletal-rich structure known as the growth cone, which detects and integrates signals to reach its final destination. The guidance cues “signals” bind their receptors, activating signaling cascades that result in the regulation of the growth cone cytoskeleton, defining growth cone advance, pausing, turning, or collapse. Even though much is known about guidance cues and their isolated mechanisms during nervous system development, there is still a gap in the understanding of the crosstalk between them, and about what happens after nervous system injuries. After neuronal injuries in mammals, only axons in the peripheral nervous system are able to regenerate, while the ones from the central nervous system fail to do so. Therefore, untangling the guidance cues mechanisms, as well as their behavior and characterization after axotomy and regeneration, are of special interest for understanding and treating neuronal injuries. In this review, we present findings on growth cone guidance and canonical guidance cues mechanisms, followed by a description and comparison of growth cone pathfinding mechanisms after axotomy, in regenerative and non-regenerative animal models. Full article
(This article belongs to the Special Issue Role of Neuronal Guidance Cues in Inflammation and Vascular Biology)
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19 pages, 2119 KiB  
Review
The Role of Semaphorins in Metabolic Disorders
by Qiongyu Lu and Li Zhu
Int. J. Mol. Sci. 2020, 21(16), 5641; https://doi.org/10.3390/ijms21165641 - 06 Aug 2020
Cited by 20 | Viewed by 4569
Abstract
Semaphorins are a family originally identified as axonal guidance molecules. They are also involved in tumor growth, angiogenesis, immune regulation, as well as other biological and pathological processes. Recent studies have shown that semaphorins play a role in metabolic diseases including obesity, adipose [...] Read more.
Semaphorins are a family originally identified as axonal guidance molecules. They are also involved in tumor growth, angiogenesis, immune regulation, as well as other biological and pathological processes. Recent studies have shown that semaphorins play a role in metabolic diseases including obesity, adipose inflammation, and diabetic complications, including diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, diabetic wound healing, and diabetic osteoporosis. Evidence provides mechanistic insights regarding the role of semaphorins in metabolic diseases by regulating adipogenesis, hypothalamic melanocortin circuit, immune responses, and angiogenesis. In this review, we summarize recent progress regarding the role of semaphorins in obesity, adipose inflammation, and diabetic complications. Full article
(This article belongs to the Special Issue Role of Neuronal Guidance Cues in Inflammation and Vascular Biology)
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19 pages, 772 KiB  
Review
Ephs and Ephrins in Adult Endothelial Biology
by Dianne Vreeken, Huayu Zhang, Anton Jan van Zonneveld and Janine M. van Gils
Int. J. Mol. Sci. 2020, 21(16), 5623; https://doi.org/10.3390/ijms21165623 - 06 Aug 2020
Cited by 17 | Viewed by 3054
Abstract
Eph receptors and their ephrin ligands are important guidance molecules during neurological and vascular development. In recent years, it has become clear that the Eph protein family remains functional in adult physiology. A subset of Ephs and ephrins is highly expressed by endothelial [...] Read more.
Eph receptors and their ephrin ligands are important guidance molecules during neurological and vascular development. In recent years, it has become clear that the Eph protein family remains functional in adult physiology. A subset of Ephs and ephrins is highly expressed by endothelial cells. As endothelial cells form the first barrier between the blood and surrounding tissues, maintenance of a healthy endothelium is crucial for tissue homeostasis. This review gives an overview of the current insights of the role of ephrin ligands and receptors in endothelial function and leukocyte recruitment in the (patho)physiology of adult vascular biology. Full article
(This article belongs to the Special Issue Role of Neuronal Guidance Cues in Inflammation and Vascular Biology)
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18 pages, 1926 KiB  
Review
Emerging Roles for Neuropilin-2 in Cardiovascular Disease
by Jennifer L. Harman, Jacob Sayers, Chey Chapman and Caroline Pellet-Many
Int. J. Mol. Sci. 2020, 21(14), 5154; https://doi.org/10.3390/ijms21145154 - 21 Jul 2020
Cited by 14 | Viewed by 5233
Abstract
Cardiovascular disease, the leading cause of death worldwide, is predominantly associated with atherosclerosis. Atherosclerosis is a chronic inflammatory disease characterised by the narrowing of large to medium-sized arteries due to a build-up of plaque. Atherosclerotic plaque is comprised of lipids, extracellular matrix, and [...] Read more.
Cardiovascular disease, the leading cause of death worldwide, is predominantly associated with atherosclerosis. Atherosclerosis is a chronic inflammatory disease characterised by the narrowing of large to medium-sized arteries due to a build-up of plaque. Atherosclerotic plaque is comprised of lipids, extracellular matrix, and several cell types, including endothelial, immune, and vascular smooth muscle cells. Such narrowing of the blood vessels can itself restrict blood flow to vital organs but most severe clinical complications, including heart attacks and strokes, occur when lesions rupture, triggering the blood to clot and obstructing blood flow further down the vascular tree. To circumvent such obstructions, percutaneous coronary intervention or bypass grafts are often required; however, re-occlusion of the treated artery frequently occurs. Neuropilins (NRPs), a multifunctional family of cell surface co-receptors, are expressed by endothelial, immune, and vascular smooth muscle cells and are regulators of numerous signalling pathways within the vasculature. Here, we review recent studies implicating NRP2 in the development of occlusive vascular diseases and discuss how NRP2 could be targeted for therapeutic intervention. Full article
(This article belongs to the Special Issue Role of Neuronal Guidance Cues in Inflammation and Vascular Biology)
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