Endothelial Neuropilin-1: a multifaced signal transducer with an emerging role in inflammation and atherosclerosis beyond angiogenesis.

Neuropilin-1 (NRP1) is a transmembrane glycoprotein expressed by several cell types including, neurons, endothelial cells (ECs), smooth muscle cells, cardiomyocytes and immune cells comprising macrophages, dendritic cells and T cell subsets. Since NRP1 discovery in 1987 as an adhesion molecule in the frog nervous system, more than 2300 publications on PubMed investigated the function of NRP1 in physiological and pathological contexts. NRP1 has been characterised as a coreceptor for class 3 semaphorins and several members of the vascular endothelial growth factor (VEGF) family. Because the VEGF family is the main regulator of blood and lymphatic vessel growth in addition to promoting neurogenesis, neuronal patterning, neuroprotection and glial growth, the role of NRP1 in these biological processes has been extensively investigated. It is now established that NRP1 promotes the physiological growth of new vessels from pre-existing ones in the process of angiogenesis. Furthermore, several studies have shown that NRP1 mediates signalling pathways regulating pathological vascular growth in ocular neovascular diseases and tumour development. Less defined are the roles of NRP1 in maintaining the function of the quiescent established vasculature in an adult organism. This review will focus on the opposite roles of NRP1 in regulating transforming growth factor ß signalling pathways in different cell types, and on the emerging role of endothelial NRP1 as an atheroprotective, anti-inflammatory factor involved in the response of ECs to shear stress.

In silico and in vitro study of bioactive compounds of Nigella sativa for targeting neuropilins in breast cancer.

Introduction: Breast cancer poses a significant global challenge, prompting researchers to explore novel approaches for potential treatments. Material and Methods: For in vitro study we used thin layer chromatography (TAC) for phytochemical screening, total antioxidant capacity (TLC) assay for antioxidant capacity, and hemolytic activity test for toxicity of Neuropilins (NRPs). We performed bioinformatic analyses to predict protein structures, molecular docking, pharmacophore modeling, and virtual screening to reveal interactions with oncogenes. We conducted 200 ns Molecular Dynamics (MD) simulations and MMGBSA calculations to assess the complex dynamics and stability. Results: We identified phytochemical constituents in Nigella sativa leaves, including tannins, saponins, steroids, and cardiac glycosides, while phlobatannins and terpenoids were absent. The leaves contained 9.4% ± 0.04% alkaloids and 1.9% ± 0.05% saponins. Methanol extract exhibited the highest yield and antioxidant capacity, with Total Flavonoid Content at 127.51 ± 0.76 mg/100 g and Total Phenolic Content at 134.39 ± 0.589 mg GAE/100 g. Hemolysis testing showed varying degrees of hemolysis for different extracts. In-silico analysis indicated stable Neuropilin complexes with key signaling pathways relevant for anti-cancer therapy. Molecular docking scores at different possesses (0, C-50, C -80, C-120,C -150, C -200 ns) revealed strong hydrogen bonding in the complexes and showed -12.9, -11.6, and -11.2 binding Affinities (kcal/mol) to support their stability. Our MD simulations analysis at 200ns confirmed the stability of Neuropilin complexes with the signaling pathways protein PI3K. The calculated binding free energies using MMGBSA provided valuable quantitative information on ligand potency on different time steps. These findings highlight the potential health benefits of N. sativa leaves and their possible role in anti-cancer treatments targeting angiogenesis. Conclusion: Nigella sativa leaves have shown significant medical potential due to their bioactive compounds, which exhibit strong properties in supporting organogenic processes related to cancer. Furthermore, studies have highlighted the promising role of neuropilins in anticancer treatment, demonstrating stable interactions and potential as targeted therapy specifically for breast cancer.

Semaphorin 3A influences neuronal processes that are altered in patients with autism spectrum disorder: Potential diagnostic and therapeutic implications.

Autism spectrum disorder (ASD) is a pervasive disorder that most frequently manifests in early childhood and lasts for their entire lifespan. Several behavioural traits characterise the phenotype of patients with ASD, including difficulties in reciprocal social communication as well as compulsive/repetitive stereotyped verbal and non-verbal behaviours. Although multiple hypotheses have been proposed to explain the aetiology of ASD and many resources have been used to improve our understanding of ASD, several aspects remain largely unexplored. Class 3 semaphorins (SEMA3) are secreted proteins involved in the organisation of structural and functional connectivity in the brain that regulate synaptic and dendritic development. Alterations in brain connectivity and aberrant neuronal development have been described in some patients with ASD. Mutations and polymorphisms in SEMA3A and alterations in its receptors and signalling have been associated with some neurological disorders such as schizophrenia and epilepsy, which are comorbidities in ASD, but also with ASD itself. In addition, SEMA3A is a key regulator of the immune response and neuroinflammatory processes, which have been found to be dysregulated in mothers of children who develop ASD and in affected patients. In this review, we highlight neurodevelopmental-related processes in which SEMA3A is involved, which are altered in ASD, and provide a viewpoint emphasising the development of strategies targeting changes in the SEMA3A signal to identify patterns of anomalies distinctive of ASD or to predict the prognosis of affected patients.

Immune Checkpoint Neuropilins as Novel Biomarkers and Therapeutic Targets for Pancreatic Cancer.

The traditional immune checkpoint blockade therapy benefits some patients with cancer, but elicits no response in certain cancers, such as pancreatic adenocarcinoma (PAAD); thus, novel checkpoints and effective targets are required. Here, we found that there was a higher Neuropilin (NRP) expression in tumor tissues as novel immune checkpoints, which was associated with poor prognosis and pessimistic responses to immune checkpoint blockade therapy. In the tumor microenvironment of PAAD samples, NRPs were widely expressed in tumor, immune and stromal cells. The relationship of NRPs with tumor immunological features in PAAD and pan-cancer was evaluated using bioinformatics methods; it was positively correlated with the infiltration of myeloid immune cells and the expression of most immune checkpoint genes. Bioinformatics analysis, in vitro and in vivo experiments suggested that NRPs exhibit potential immune-related and immune-independent pro-tumor effects. NRPs, especially NRP1, are attractive biomarkers and therapeutic targets for cancers, particularly PAAD.

Palmitoylation regulates neuropilin-2 localization and function in cortical neurons and conveys specificity to semaphorin signaling via palmitoyl acyltransferases.

Secreted semaphorin 3F (Sema3F) and semaphorin 3A (Sema3A) exhibit remarkably distinct effects on deep layer excitatory cortical pyramidal neurons; Sema3F mediates dendritic spine pruning, whereas Sema3A promotes the elaboration of basal dendrites. Sema3F and Sema3A signal through distinct holoreceptors that include neuropilin-2 (Nrp2)/plexinA3 (PlexA3) and neuropilin-1 (Nrp1)/PlexA4, respectively. We find that Nrp2 and Nrp1 are S-palmitoylated in cortical neurons and that palmitoylation of select Nrp2 cysteines is required for its proper subcellular localization, cell surface clustering, and also for Sema3F/Nrp2-dependent dendritic spine pruning in cortical neurons, both in vitro and in vivo. Moreover, we show that the palmitoyl acyltransferase ZDHHC15 is required for Nrp2 palmitoylation and Sema3F/Nrp2-dependent dendritic spine pruning, but it is dispensable for Nrp1 palmitoylation and Sema3A/Nrp1-dependent basal dendritic elaboration. Therefore, palmitoyl acyltransferase-substrate specificity is essential for establishing compartmentalized neuronal structure and functional responses to extrinsic guidance cues.

Exploration of tumor penetrating peptide iRGD as a potential strategy to enhance tumor penetration of cancer nanotherapeutics.

Cancer therapy continues to be a huge challenge as most chemotherapeutic agents exert serious adverse effects on healthy organs. Chemotherapeutic agents lack selective targeting and even the existing target specific therapies are failing due to poor distribution into the tumor microenvironment. Nanotechnology offers multiple advantages to address the limitations encountered by conventional therapy. However, the delivery of nanotherapeutics to tumor tissue has not improved over the years partly due to the poor and inadequate distribution of nanotherapeutics into deeper tumor regions resulting in resistance and relapse. To curb the penetration concerns, iRGD was explored and found to be highly effective in improving the delivery of cancer nanomedicine. The preclinical observations are highly encouraging; however, the clinical translation is at a nascent stage. Based on this, we have made an elaborative effort to give a detailed account of various promising applications of iRGD to increase anticancer and tumor imaging potential. Importantly, we have comprehensively discussed the shortcomings and uncertainties associated with the clinical translation of iRGD-based therapeutic approaches and future directions.

Neuropilins as potential biomarkers in hepatocellular carcinoma: a systematic review of basic and clinical implications.

Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide and is characterized by complex molecular carcinogenesis. Neuropilins (NRPs) NRP1 and NRP2 are the receptors of multiple proteins involved in key signaling pathways associated with tumor progression. We aimed to systematically review all the available findings on their role in HCC. We searched the Scopus, Web of Science (WOS), PubMed, Cochrane and Embase databases for articles evaluating NRPs in preclinical or clinical HCC models. This study was registered in PROSPERO (CRD42022349774) and include 49 studies. Multiple cellular and molecular processes have been associated with one or both NRPs, indicating that they are potential diagnostic and prognostic biomarkers in HCC patients. Mainly NRP1 has been shown to promote tumor cell survival and progression by modulating several signaling pathways. NRPs mainly regulate angiogenesis, invasion and migration and have shown to induce invasion and metastasis. They also regulate the immune response and tumor microenvironment, showing a crucial interplay with the hypoxia response and microRNAs in HCC. Altogether, NRP1 and NRP2 are potential biomarkers and therapeutic targets, providing novel insight into the clinical landscape of HCC patients.

Neuropilin (NRPs) Related Pathological Conditions and Their Modulators.

Neuropilin 1 (NRP1) represents one of the two homologous neuropilins (NRP, splice variants of neuropilin 2 are the other) found in all vertebrates. It forms a transmembrane glycoprotein distributed in many human body tissues as a (co)receptor for a variety of different ligands. In addition to its physiological role, it is also associated with various pathological conditions. Recently, NRP1 has been discovered as a coreceptor for the SARS-CoV-2 viral entry, along with ACE2, and has thus become one of the COVID-19 research foci. However, in addition to COVID-19, the current review also summarises its other pathological roles and its involvement in clinical diseases like cancer and neuropathic pain. We also discuss the diversity of native NRP ligands and perform a joint analysis. Last but not least, we review the therapeutic roles of NRP1 and introduce a series of NRP1 modulators, which are typical peptidomimetics or other small molecule antagonists, to provide the medicinal chemistry community with a state-of-the-art overview of neuropilin modulator design and NRP1 druggability assessment.

Axon guidance molecules in immunometabolic diseases.

The global prevalence of metabolic diseases, such as obesity, diabetes, and atherosclerosis, is rapidly increasing and has now reached epidemic proportions. Chronic tissue inflammation is a characteristic of these metabolic diseases, indicating that immune responses are closely involved in the pathogenesis of metabolic disorders. However, the regulatory mechanisms underlying immunometabolic crosstalk in these diseases are not completely understood. Recent studies have revealed the multifaceted functions of semaphorins, originally identified as axon guidance molecules, in regulating tissue inflammation and metabolic disorders, thereby highlighting the functional coupling between semaphorin signaling and immunometabolism. In this review, we explore how semaphorin signaling transcends beyond merely guiding axons to controlling immune responses and metabolic diseases.

Vascular Endothelial Growth Factor Signaling in Models of Oxygen-Induced Retinopathy: Insights Into Mechanisms of Pathology in Retinopathy of Prematurity.

Retinopathy of prematurity (ROP) is a leading cause of blindness in children worldwide. Blindness can occur from retinal detachment caused by pathologic retinal angiogenesis into the vitreous, termed intravitreal neovascularization (IVNV). Although agents that interfere with the bioactivity of vascular endothelial growth factor (VEGF) are now used to treat IVNV, concerns exist regarding the identification of optimal doses of anti-VEGF for individual infants and the effect of broad VEGF inhibition on physiologic angiogenesis in external organs or in the retina of a preterm infant. Therefore, it is important to understand VEGF signaling in both physiologic and pathologic angiogenesis in the retina. In this manuscript, we review the role of receptors that interact with VEGF in oxygen-induced retinopathy (OIR) models that represent features of ROP pathology. Specifically, we discuss our work regarding the regulation of VEGFR2 signaling in retinal endothelial cells to not only reduce severe ROP but also facilitate physiologic retinal vascular and neuronal development.

Neuropilin-1: A Key Protein to Consider in the Progression of Pediatric Brain Tumors.

Neuropilins are transmembrane glycoproteins that play important roles in cardiovascular and neuronal development, as well as in immunological system regulations. NRP1 functions as a co-receptor, binding numerous ligands, such as SEMA 3 or VEGF and, by doing so, reinforcing their signaling pathways and can also interface with the cytoplasmic protein synectin. NRP1 is expressed in many cancers, such as brain cancers, and is associated with poor prognosis. The challenge today for patients with pediatric brain tumors is to improve their survival rate while minimizing the toxicity of current treatments. The aim of this review is to highlight the involvement of NRP1 in pediatric brain cancers, focusing essentially on the roles of NRP1 in cancer stem cells and in the regulation of the immune system. For this purpose, recent literature and tumor databases were analyzed to show correlations between NRP1 and CD15 (a stem cancer cells marker), and between NRP1 and PDL1, for various pediatric brain tumors, such as high- and low-grade gliomas, medulloblastomas, and ependymomas. Finally, this review suggests a relevant role for NRP1 in pediatric brain tumors progression and identifies it as a potential diagnostic or therapeutic target to improve survival and life quality of these young patients.

Perturbation of semaphorin and VEGF signaling in ACDMPV lungs due to FOXF1 deficiency.

BACKGROUND: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare lethal congenital lung disorder in neonates characterized by severe progressive respiratory failure and refractory pulmonary hypertension, resulting from underdevelopment of the peripheral pulmonary tree. Causative heterozygous single nucleotide variants (SNVs) or copy-number variant (CNV) deletions involving FOXF1 or its distant lung-specific enhancer on chromosome 16q24.1 have been identified in 80-90% of ACDMPV patients. FOXF1 maps closely to and regulates the oppositely oriented FENDRR, with which it also shares regulatory elements. METHODS: To better understand the transcriptional networks downstream of FOXF1 that are relevant for lung organogenesis, using RNA-seq, we have examined lung transcriptomes in 12 histopathologically verified ACDMPV patients with or without pathogenic variants in the FOXF1 locus and analyzed gene expression profile in FENDRR-depleted fetal lung fibroblasts, IMR-90. RESULTS: RNA-seq analyses in ACDMPV neonates revealed changes in the expression of several genes, including semaphorins (SEMAs), neuropilin 1 (NRP1), and plexins (PLXNs), essential for both epithelial branching and vascular patterning. In addition, we have found deregulation of the vascular endothelial growth factor (VEGF) signaling that also controls pulmonary vasculogenesis and a lung-specific endothelial gene TMEM100 known to be essential in vascular morphogenesis. Interestingly, we have observed a substantial difference in gene expression profiles between the ACDMPV samples with different types of FOXF1 defect. Moreover, partial overlap between transcriptome profiles of ACDMPV lungs with FOXF1 SNVs and FENDRR-depleted IMR-90 cells suggests contribution of FENDRR to ACDMPV etiology. CONCLUSIONS: Our transcriptomic data imply potential crosstalk between several lung developmental pathways, including interactions between FOXF1-SHH and SEMA-NRP or VEGF/VEGFR2 signaling, and provide further insight into complexity of lung organogenesis in humans.

SEMAPHORINS and their receptors: focus on the crosstalk between melanoma and hypoxia.

Hypoxia, a condition of oxygen deprivation, is considered a hallmark of tumor microenvironment regulating several pathways and promoting cancer progression and resistance to therapy. Semaphorins, a family of about 20 secreted, transmembrane and GPI-linked glycoproteins, and their cognate receptors (plexins and neuropilins) play a pivotal role in the crosstalk between cancer and stromal cells present in the tumor microenvironment. Many studies reported that some semaphorins are involved in the development of a permissive tumor niche, guiding cell-cell communication and, consequently, the development and progression, as well as the response to therapy, of different cancer histotypes, including melanoma.In this review we will summarize the state of art of semaphorins regulation by hypoxic condition in cancer with different origin. We will also describe evidence about the ability of semaphorins to affect the expression and activity of transcription factors activated by hypoxia, such as hypoxia-inducible factor-1. Finally, we will focus our attention on findings reporting the role of semaphorins in melanocytes transformation, melanoma progression and response to therapy. Further studies are necessary to understand the mechanisms through which semaphorins induce their effect and to shed light on the possibility to use semaphorins or their cognate receptors as prognostic markers and/or therapeutic targets in melanoma or other malignancies.

Role of Neuronal Guidance Cues in the Pathophysiology of Obesity: A Peripheral and Central Overview.

Obesity is associated with an exacerbated synthesis and secretion of several molecules, which culminates in chronic low-grade inflammation and insulin resistance. Such conditions affect molecular and physiological responses of several organs and, if not resolved, predispose the obese patients to other diseases such as Type 2 diabetes, atherosclerosis, cancer, neural injuries, and cognitive impairments. A microenvironment with an excess of pro-inflammatory cytokines released by different cells, including immune and adipose cells lead to metabolic and non-metabolic diseases during obesity. In this context, the role of neuronal guidance cues named netrin, semaphorin and ephrin is novel. Specifically, the available literature indicates that besides their classic role as molecules that guide the axon to its target site, the neuronal guidance cues exhibit immunomodulatory functions from adipose tissue to the neural environment. In the current narrative review, we discuss the participation of the neuronal guidance cues on the physiology and pathophysiology of obesity. We also discuss the feedback loop of obesity on the netrin, semaphorin and ephrin functions that impair the structure and function of the brain. The integrative view of the neuronal guidance cues can be relevant in designing new treatments focus on attenuating metabolic and immune disorders in obese patients and reduce the risk of acquiring diseases such as Type 2 diabetes, atherosclerosis, cancer, and neural injuries.

The role of immune semaphorins in the pathogenesis of multiple sclerosis: Potential therapeutic targets.

The immune and nervous systems possess a highly intricate network of synaptic connections, shared messenger molecules, and exquisite communication ways, allowing intercellular signal transduction. The semaphorins (Semas) were initially identified as axonal guidance molecules in the development of the nervous system but later were found to be implicated also in regulating the immune system, known in this case as the "immune Semas" or "immunoregulatory Semas". Increasingly, these molecules are involved in multiple aspects of both physiological and pathological immune responses and were recently indicated to take part in various immunological disorders, encompassing allergy, cancer, and autoimmunity. Semas transduce signals by connecting to their cognate receptors, namely, plexins and neuropilins. Some of them, like Sema-3F, have been found to function as the inducer of the remyelination process whereas some others, like Sema-3A and Sema-4D, act to inhibit this process, either directly or indirectly. Besides, Sema-4A is crucial to the differentiation of T helper type 1 (Th1) and Th17 cells that are potentially involved in the pathogenesis of multiple sclerosis (MS), an autoimmune disease of the central nervous system. This review aims to reveal the role of immune Semas in the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis, focusing on the therapeutic usages of these molecules to treat this neurodegenerative disease.

Neuropilin 1 and Neuropilin 2 gene invalidation or pharmacological inhibition reveals their relevance for the treatment of metastatic renal cell carcinoma.

BACKGROUND: Despite the improvement of relapse-free survival mediated by anti-angiogenic drugs like sunitinib (Sutent®), or by combinations of anti-angiogenic drugs with immunotherapy, metastatic clear cell Renal Cell Carcinoma (mccRCC) remain incurable. Hence, new relevant treatments are urgently needed. The VEGFs coreceptors, Neuropilins 1, 2 (NRP1, 2) are expressed on several tumor cells including ccRCC. We analyzed the role of the VEGFs/NRPs signaling in ccRCC aggressiveness and evaluated the relevance to target this pathway. METHODS: We correlated the NRP1, 2 levels to patients' survival using online available data base. Human and mouse ccRCC cells were knocked-out for the NRP1 and NRP2 genes by a CRISPR/Cas9 method. The number of metabolically active cells was evaluated by XTT assays. Migration ability was determined by wound closure experiments and invasion ability by using Boyden chamber coated with collagen. Production of VEGFA and VEGFC was evaluated by ELISA. Experimental ccRCC were generated in immuno-competent/deficient mice. The effects of a competitive inhibitor of NRP1, 2, NRPa-308, was tested in vitro and in vivo with the above-mentioned tests and on experimental ccRCC. NRPa-308 docking was performed on both NRPs. RESULTS: Knock-out of the NRP1 and NRP2 genes inhibited cell metabolism and migration and stimulated the expression of VEGFA or VEGFC, respectively. NRPa-308 presented a higher affinity for NRP2 than for NRP1. It decreased cell metabolism and migration/invasion more efficiently than sunitinib and the commercially available NRP inhibitor EG00229. NRPa-308 presented a robust inhibition of experimental ccRCC growth in immunocompetent and immunodeficient mice. Such inhibition was associated with decreased expression of several pro-tumoral factors. Analysis of the TCGA database showed that the NRP2 pathway, more than the NRP1 pathway correlates with tumor aggressiveness only in metastatic patients. CONCLUSIONS: Our study strongly suggests that inhibiting NRPs is a relevant treatment for mccRCC patients in therapeutic impasses and NRPa-308 represents a relevant hit.

Neuropilins, as Relevant Oncology Target: Their Role in the Tumoral Microenvironment.

Angiogenesis is one of the key mechanisms involved in tumor growth and metastatic dissemination. The vascular endothelial growth factor (VEGF) and its receptors (VEGFR) represent one of the major signaling pathways which mediates angiogenesis. The VEGF/VEGFR axis was intensively targeted by monoclonal antibodies or by tyrosine kinase inhibitors to destroy the tumor vascular network. By inhibiting oxygen and nutrient supply, this strategy was supposed to cure cancers. However, despite a lengthening of the progression free survival in several types of tumors including colon, lung, breast, kidney, and ovarian cancers, modest improvements in overall survival were reported. Anti-angiogenic therapies targeting VEGF/VEGFR are still used in colon and ovarian cancer and remain reference treatments for renal cell carcinoma. Although the concept of inhibiting angiogenesis remains relevant, new targets need to be discovered to improve the therapeutic index of anti-VEGF/VEGFR. Neuropilin 1 and 2 (NRP1/2), initially described as neuronal receptors, stimulate angiogenesis, lymphangiogenesis and immune tolerance. Moreover, overexpression of NRPs in several tumors is synonymous of patients' shorter survival. This article aims to overview the different roles of NRPs in cells constituting the tumor microenvironment to highlight the therapeutic relevance of their targeting.

Characterization of Class-3 Semaphorin Receptors, Neuropilins and Plexins, as Therapeutic Targets in a Pan-Cancer Study.

Class-3 semaphorins (SEMA3s), initially characterized as axon guidance cues, have been recognized as key regulators for immune responses, angiogenesis, tumorigenesis and drug responses. The functions of SEMA3s are attributed to the activation of downstream signaling cascades mainly mediated by cell surface receptors neuropilins (NRPs) and plexins (PLXNs), yet their roles in human cancers are not completely understood. Here, we provided a detailed pan-cancer analysis of NRPs and PLXNs in their expression, and association with key signal transducers, patient survival, tumor microenvironment (TME), and drug responses. The expression of NRPs and PLXNs were dysregulated in many cancer types, and the majority of them were further dysregulated in metastatic tumors, indicating a role in metastatic progression. Importantly, the expression of these genes was frequently associated with key transducers, patient survival, TME, and drug responses; however, the direction of the association varied for the particular gene queried and the specific cancer type/subtype tested. Specifically, NRP1, NRP2, PLXNA1, PLXNA3, PLXNB3, PLXNC1, and PLXND1 were primarily associated with aggressive phenotypes, whereas the rest were more associated with favorable prognosis. These data highlighted the need to study each as a separate entity in a cancer type- and subtype-dependent manner.

NRP2 as an Emerging Angiogenic Player; Promoting Endothelial Cell Adhesion and Migration by Regulating Recycling of α5 Integrin.

Angiogenesis relies on the ability of endothelial cells (ECs) to migrate over the extracellular matrix via integrin receptors to respond to an angiogenic stimulus. Of the two neuropilin (NRP) orthologs to be identified, both have been reported to be expressed on normal blood and lymphatic ECs, and to play roles in the formation of blood and lymphatic vascular networks during angiogenesis. Whilst the role of NRP1 and its interactions with integrins during angiogenesis has been widely studied, the role of NRP2 in ECs is poorly understood. Here we demonstrate that NRP2 promotes Rac-1 mediated EC adhesion and migration over fibronectin (FN) matrices in a mechanistically distinct fashion to NRP1, showing no dependence on ß3 integrin (ITGB3) expression, or VEGF stimulation. Furthermore, we highlight evidence of a regulatory crosstalk between NRP2 and α5 integrin (ITGA5) in ECs, with NRP2 depletion eliciting an upregulation of ITGA5 expression and disruptions in ITGA5 cellular organization. Finally, we propose a mechanism whereby NRP2 promotes ITGA5 recycling in ECs; NRP2 depleted ECs were found to exhibit reduced levels of total ITGA5 subunit recycling compared to wild-type (WT) ECs. Our findings expose NRP2 as a novel angiogenic player by promoting ITGA5-mediated EC adhesion and migration on FN.

Semaphorins in Angiogenesis and Autoimmune Diseases: Therapeutic Targets?

The axonal guidance molecules, semaphorins, have been described to function both physiologically and pathologically outside of the nervous system. In this review, we focus on the vertebrate semaphorins found in classes 3 through 7 and their roles in vascular development and autoimmune diseases. Recent studies indicate that while some of these vertebrate semaphorins promote angiogenesis, others have an angiostatic function. Since some semaphorins are also expressed by different immune cells and are known to modulate immune responses, they have been implicated in autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis. We conclude this review by addressing strategies targeting semaphorins as potential therapeutic agents for angiogenesis and autoimmune diseases.