Class-3 semaphorins: Potent multifunctional modulators for angiogenesis-associated diseases

Jiao, Bo; Liu, Shiyang; Tan, Xi; Lu, Pei-Hua; Wang, Danning; Xu, Hui

doi:10.1016/j.biopha.2021.111329

Cited by 21 publications

(15 citation statements)

References 99 publications

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“…In recent years, increasing studies have demonstrated that endothelial cells express neuropilins, plexins, and roundabouts, all axon guidance molecule receptors that interact with their soluble neuroendothelial ligands, such as semaphorins and slits, to control endothelial cell sprouting and angiogenesis [ 9 , 35 ]. Given their regulatory role in angiogenesis, these molecules have been implicated in the pathophysiology of different disorders including cancer, diabetic retinopathy, and nephropathy, as well as autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus [ 9 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. As far as SSc is concerned, our previous in vitro findings demonstrated a significant contribution of the neurovascular guidance molecules NRP1, Sema3E, and Slit2 in the dysregulation of the angiogenic process [ 9 , 18 , 20 , 21 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, it has been shown that, during their development, the nervous and vascular systems communicate with each other in a neurovascular crosstalk, with vessels producing signals that are able to attract axons to track alongside the pioneer vessels and, in turn, nerves releasing signals able to guide blood vessel growth [ 6 , 7 , 8 , 9 , 10 ]. In this context, several molecules with attractive and repulsive properties, here referred to as neurovascular guidance molecules, have been reported to regulate the sprouting of both nerves and blood vessels [ 8 , 9 , 10 ], and to be involved in different pathologic processes including tumor growth/metastasis, nephropathy, as well as autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. As far as SSc is concerned, members of semaphorin/plexin/neuropilin and slit/roundabout families have been recently implicated in SSc-related disturbed neuroendothelial control of vascular tone, peripheral microvasculopathy, and defective angiogenesis, with their circulating levels being significantly associated with different vascular disease manifestations [ 9 , 18 , 19 , 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

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Circulating Neurovascular Guidance Molecules and Their Relationship with Peripheral Microvascular Impairment in Systemic Sclerosis

Romano

Rosa

Fioretto

et al. 2022

Life

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Systemic sclerosis (SSc, scleroderma) is a complex connective tissue disease whose earliest clinical manifestations are microvascular tone dysregulation and peripheral microcirculatory abnormalities. Following previous evidence of an association between circulating neurovascular guidance molecules and SSc disturbed angiogenesis, here, we measured the levels of soluble neuropilin 1 (sNRP1), semaphorin 3E (Sema3E), and Slit2 by enzyme-linked immunosorbent assay in serum samples from a large case series of 166 SSc patients vs. 110 healthy controls. We focused on their possible correlation with vascular disease clinical features and applied logistic regression analysis to determine which of them could better reflect disease activity and severity. Our results demonstrate that, in SSc: (i) sNRP1 is significantly decreased, with lower sNRP1 serum levels correlating with the severity of nailfold videocapillaroscopy (NVC) abnormalities and the presence of ischemic digital ulcers (DUs); (ii) both Sema3E and Slit2 are increased, with Sema3E better reflecting early NVC abnormalities; and (iii) higher Sema3E correlates with the absence of DUs, while augmented Slit2 associates with the presence of DUs. Receiver operator characteristics curve analysis revealed that both circulating sNRP1 and Sema3E show a moderate diagnostic accuracy. Moreover, logistic regression analysis allowed to identify sNRP1 and Sema3E as more suitable independent biomarkers reflecting the activity and severity of SSc-related peripheral microvasculopathy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Circulating Neurovascular Guidance Molecules and Their Relationship with Peripheral Microvascular Impairment in Systemic Sclerosis

Romano

Rosa

Fioretto

et al. 2022

Life

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“…However, CS-PGs inhibit neuritogenesis ( Figure 2 ). Besides acting as signalling molecules providing axonal guidance cues during neural development, the semaphorins also have roles in immune regulation, angiogenesis and invasive tumour growth [ 129 , 130 , 131 , 132 , 133 ]. The main functional receptor for semaphorins are the large single pass transmembrane plexins.…”

Section: The Semaphorinsmentioning

confidence: 99%

“…Semaphorins can also undertake “reverse signalling” in which rather than acting as ligands they act as receptors and initiate a signalling response through their own cytoplasmic domains [ 129 , 130 ]. Thus, the semaphorins have multifaceted properties in neurodevelopment and in the pathological CNS following injury or disease [ 131 , 132 , 133 , 134 , 135 , 136 , 137 ].…”

Section: The Semaphorinsmentioning

confidence: 99%

The CNS/PNS Extracellular Matrix Provides Instructive Guidance Cues to Neural Cells and Neuroregulatory Proteins in Neural Development and Repair

Melrose

Hayes

Bix

2021

IJMS

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Background. The extracellular matrix of the PNS/CNS is unusual in that it is dominated by glycosaminoglycans, especially hyaluronan, whose space filling and hydrating properties make essential contributions to the functional properties of this tissue. Hyaluronan has a relatively simple structure but its space-filling properties ensure micro-compartments are maintained in the brain ultrastructure, ensuring ionic niches and gradients are maintained for optimal cellular function. Hyaluronan has cell-instructive, anti-inflammatory properties and forms macro-molecular aggregates with the lectican CS-proteoglycans, forming dense protective perineuronal net structures that provide neural and synaptic plasticity and support cognitive learning. Aims. To highlight the central nervous system/peripheral nervous system (CNS/PNS) and its diverse extracellular and cell-associated proteoglycans that have cell-instructive properties regulating neural repair processes and functional recovery through interactions with cell adhesive molecules, receptors and neuroregulatory proteins. Despite a general lack of stabilising fibrillar collagenous and elastic structures in the CNS/PNS, a sophisticated dynamic extracellular matrix is nevertheless important in tissue form and function. Conclusions. This review provides examples of the sophistication of the CNS/PNS extracellular matrix, showing how it maintains homeostasis and regulates neural repair and regeneration.

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“…In addition, Sema3A can also function as chemo-attractive agent, stimulating the growth of apical dendrites [ 15 ]. Moreover, class-3 Semaphorins also play a role in many processes outside the nervous system, as tumor progression or suppression [ 16 , 17 ] or in the immune system [ 18 , 19 ] and are attracting much attention as potential therapeutic targets [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Semaphorin 3A—Glycosaminoglycans Interaction as Therapeutic Target for Axonal Regeneration

et al. 2021

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Semaphorin 3A (Sema3A) is a cell-secreted protein that participates in the axonal guidance pathways. Sema3A acts as a canonical repulsive axon guidance molecule, inhibiting CNS regenerative axonal growth and propagation. Therefore, interfering with Sema3A signaling is proposed as a therapeutic target for achieving functional recovery after CNS injuries. It has been shown that Sema3A adheres to the proteoglycan component of the extracellular matrix (ECM) and selectively binds to heparin and chondroitin sulfate-E (CS-E) glycosaminoglycans (GAGs). We hypothesize that the biologically relevant interaction between Sema3A and GAGs takes place at Sema3A C-terminal polybasic region (SCT). The aims of this study were to characterize the interaction of the whole Sema3A C-terminal polybasic region (Sema3A 725–771) with GAGs and to investigate the disruption of this interaction by small molecules. Recombinant Sema3A basic domain was produced and we used a combination of biophysical techniques (NMR, SPR, and heparin affinity chromatography) to gain insight into the interaction of the Sema3A C-terminal domain with GAGs. The results demonstrate that SCT is an intrinsically disordered region, which confirms that SCT binds to GAGs and helps to identify the specific residues involved in the interaction. NMR studies, supported by molecular dynamics simulations, show that a new peptoid molecule (CSIC02) may disrupt the interaction between SCT and heparin. Our structural study paves the way toward the design of new molecules targeting these protein–GAG interactions with potential therapeutic applications.

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Class-3 semaphorins: Potent multifunctional modulators for angiogenesis-associated diseases

Cited by 21 publications

References 99 publications

Circulating Neurovascular Guidance Molecules and Their Relationship with Peripheral Microvascular Impairment in Systemic Sclerosis

Circulating Neurovascular Guidance Molecules and Their Relationship with Peripheral Microvascular Impairment in Systemic Sclerosis

The CNS/PNS Extracellular Matrix Provides Instructive Guidance Cues to Neural Cells and Neuroregulatory Proteins in Neural Development and Repair

Semaphorin 3A—Glycosaminoglycans Interaction as Therapeutic Target for Axonal Regeneration

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