Neuropeptide Vasoactive Intestinal Peptide Research Articles

Vasoactive intestinal peptide exerts an osteoinductive effect in human mesenchymal stem cells.

Several neuropeptides present in bone tissues, produced by nerve fibers and bone cells, have been reported to play a role in regulating the fine-tuning of osteoblast and osteoclast functions to maintain bone homeostasis. This study aims to characterize the influence of the neuropeptide vasoactive intestinal peptide (VIP) on the differentiation process of human mesenchymal stem cells (MSCs) into osteoblasts and on their anabolic function. We describe the mRNA and protein expression profile of VIP and its receptors in MSCs as they differentiate into osteoblasts, suggesting the presence of an autocrine signaling pathway in these cells. Our findings reveal that VIP enhances the expression of early osteoblast markers in MSCs under osteogenic differentiation and favors both bone matrix formation and proper cytoskeletal reorganization. Finally, our data suggest that VIP could be exerting a direct modulatory role on the osteoblast to osteoclast signaling by downregulating the receptor activator of nuclear factor-κB ligand/osteoprotegerin ratio. These results highlight the potential of VIP as an osteoinductive differentiation factor, emerging as a key molecule in the maintenance of human bone homeostasis.

Effects of the Neuropeptides Pituitary Adenylate Cyclase Activating Polypeptide and Vasoactive Intestinal Peptide in Male Fertility.

Background and Objectives: The neuroendocrine system plays a crucial role in regulating various bodily functions, including reproduction, with evidence suggesting its significant involvement in male fertility and sperm development. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) are expressed in both male and female reproductive tissues, influencing penile erection and regulating steroidogenesis in males. Therefore, our study aimed to compare the protein levels of VIP and PACAP in seminal plasma between healthy controls and sub-fertile patients. Additionally, we sought to correlate the levels of these biomarkers with clinical, functional, and laboratory findings in the participants. Materials and Methods: The study included a total of 163 male participants for analysis. The participants were further stratified into subgroups of fertile and sub-fertile men of four subgroups according to the 2021 WHO guidelines. Seminal plasma concentrations of the neuropeptides VIP and PACAP were measured using human enzyme-linked immunosorbent assay technique. Results: The findings showed statistically significant differences in total sperm count, sperm concentration, total motility, and vitality (p < 0.001) between the fertile group and the sub-fertile group. Specifically, significant differences found between healthy males and oligoasthenospermic patients (p = 0.002), and between asthenospermic and oligoasthenospermic patients (p = 0.039). An ROC analysis showed associated sensitivity and specificity values of 62.2% and 55.6%, respectively, to PACAP seminal levels differentiated between sub-fertile patients from fertile males (p = 0.028). No significant difference in seminal levels of VIP was found between the sub-fertile and fertile groups. Conclusions: Previous research leads to the point of PACAP active involvement in spermatogenesis. In accordance to our study, in human semen samples, we have seen a significance change in PACAP levels amongst patients with low sperm count or with both low sperm count and low motility, hinting at its contribution and acting as a possible factor in this complex process. Thus, alterations in the levels or actions of these neuropeptides have been associated with certain reproductive disorders in males.

Involvement of Vasoactive Intestinal Peptide Family Members in Diabetic Keratopathy

Diabetic keratopathy (DK) is a common ocular complication of diabetes, characterized by alteration of the normal wound-healing mechanism, reduction of epithelial hemidesmosomes, disruption of the basement membrane, impaired barrier function, reduced corneal sensitivity, corneal ulcers, and corneal edema. The limited number of clinical studies do not allow a full characterization of the pathophysiology of DK and, until now, effective therapeutic approaches have not been available. However, in recent years, neuropeptides gained great attention for their biochemical characteristics and therapeutic potential. This review focuses on the role of neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) in the eye and, in particular, in the cornea, in physiological conditions, or during DK, by providing an overview of this diabetes mellitus complication.

Inflammatory profile of keratoconic corneal epithelium

BackgroundRecent studies have presented inflammatory features on keratoconus (KC) and many inflammatory markers are described in the tears of patients with this disease. The KC pathogenesis is still unknown just like the correlation with inflammatory patterns. However, environmental and genetic issues may be part of the progress of KC. In addition, some systemic features, such as allergy and obesity, seem to be related to the progression of KC. Our purpose was to evaluate the neuropeptides vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), chemokines ligand 2 (CCL-2) and 5 (CCL-5), and interleukins 6 (IL-6) and 8 (IL-8) on corneal epithelial cells and blood of patients with KC and in healthy controls. In addition, the neutrophil-to-lymphocyte ratio (NLR) was evaluated to predict inflammation.MethodsThis including prospective observational study included 32 KC patients who underwent corneal crosslinking (CXL) and 32 control patients who underwent photorefractive keratectomy (PRK). Patients’ corneal epithelial cells were removed surgically, and blood (buffy coat) was analyzed. Samples in triplicate were evaluated on rt-PCR for neuropeptides (VIP e NPY), interleukins (IL-6 e IL-8), and chemokines (CCL-2 and CCL-5).ResultsOur study showed statistically higher CCL-5 and IL-8 on corneal epithelial cells in patients with KC. Blood cells were statistically higher in VIP and NPY in the KC group. Interleukin-8 on blood cells was statistically significant in KC’S group; for CCL-2 and CCL-5 they were statistically lower in patients with KC compared with controls. NLR showed no difference between the groups.ConclusionsOur data support the findings of other studies that suggested altering KC status, such as inflammatory corneal disease. The presence of IL-8 in the cornea and blood samples of KC’s group suggested systemic disease with a possible local or repercussion action. Further studies are warranted to elucidate KC pathogenesis and its correlation to systemic disease.

A negative trial for vasoactive intestinal peptide in COVID-19-associated acute hypoxaemic respiratory failure

A negative trial for vasoactive intestinal peptide in COVID-19-associated acute hypoxaemic respiratory failure

Astrocytic control of extracellular GABA drives circadian timekeeping in the suprachiasmatic nucleus

The hypothalamic suprachiasmatic nucleus (SCN) is the master mammalian circadian clock. Its cell-autonomous timing mechanism, a transcriptional/translational feedback loop (TTFL), drives daily peaks of neuronal electrical activity, which in turn control circadian behavior. Intercellular signals, mediated by neuropeptides, synchronize and amplify TTFL and electrical rhythms across the circuit. SCN neurons are GABAergic, but the role of GABA in circuit-level timekeeping is unclear. How can a GABAergic circuit sustain circadian cycles of electrical activity, when such increased neuronal firing should become inhibitory to the network? To explore this paradox, we show that SCN slices expressing the GABA sensor iGABASnFR demonstrate a circadian oscillation of extracellular GABA ([GABA]e) that, counterintuitively, runs in antiphase to neuronal activity, with a prolonged peak in circadian night and a pronounced trough in circadian day. Resolving this unexpected relationship, we found that [GABA]e is regulated by GABA transporters (GATs), with uptake peaking during circadian day, hence the daytime trough and nighttime peak. This uptake is mediated by the astrocytically expressed transporter GAT3 (Slc6a11), expression of which is circadian-regulated, being elevated in daytime. Clearance of [GABA]e in circadian day facilitates neuronal firing and is necessary for circadian release of the neuropeptide vasoactive intestinal peptide, a critical regulator of TTFL and circuit-level rhythmicity. Finally, we show that genetic complementation of the astrocytic TTFL alone, in otherwise clockless SCN, is sufficient to drive [GABA]e rhythms and control network timekeeping. Thus, astrocytic clocks maintain the SCN circadian clockwork by temporally controlling GABAergic inhibition of SCN neurons.

Vasoactive intestinal peptide receptor 2 signaling promotes breast cancer cell proliferation by enhancing the ERK pathway

Vasoactive intestinal peptide (VIP) receptor 2 (VIPR2) is a class B G protein-coupled receptor with the neuropeptide VIP as a ligand. Increased VIPR2 mRNA expression and/or VIPR2 gene copy number has been documented in several cancers including breast carcinoma. However, the pathophysiological role of increased VIPR2 in the proliferation of breast cancer cells remains largely unknown. In this study, we found that VIPR2 overexpression in MCF-7 and MDA-MB-231 cells, human breast cancer cell lines, promoted cell proliferation. Increased VIPR2 also exacerbated intraperitoneal proliferation of breast cancer MDA-MB-231 cells in a tumor nude mouse model in vivo. Treatment with KS-133, a VIPR2-selective antagonist peptide, significantly inhibited VIP-induced cell proliferation in VIPR2-overexpressing MCF-7 and MDA-MB-231 cells. Overexpressed VIPR2 caused increases in the levels of cAMP and phosphorylated extracellular signal-regulated kinase (ERK), which involves a VIPR2 signaling pathway through Gs protein. Additionally, phosphorylation of vasodilator-stimulated phosphoprotein (Ser157) and cAMP response element binding protein (Ser133) in VIPR2-overexpressing MCF-7 cells was greater than that in control cells, suggesting the increased PKA activity. Moreover, an inhibitor of mitogen-activated protein kinase kinase, U0126, attenuated tumor proliferation in exogenous VIPR2-expressing MCF-7 and MDA-MB-231 cells at the same level as observed in EGFP-expressing cells treated with U0126. Together, these findings suggest that VIPR2 controls breast tumor growth by regulating the cAMP/PKA/ERK signaling pathway, and the excessive expression of VIPR2 may lead to an exacerbation of breast carcinoma.

Targeting vasoactive intestinal peptide-mediated signaling enhances response to immune checkpoint therapy in pancreatic ductal adenocarcinoma

A paucity of effector T cells within tumors renders pancreatic ductal adenocarcinoma (PDAC) resistant to immune checkpoint therapies. While several under-development approaches target immune-suppressive cells in the tumor microenvironment, there is less focus on improving T cell function. Here we show that inhibiting vasoactive intestinal peptide receptor (VIP-R) signaling enhances anti-tumor immunity in murine PDAC models. In silico data mining and immunohistochemistry analysis of primary tumors indicate overexpression of the neuropeptide vasoactive intestinal peptide (VIP) in human PDAC tumors. Elevated VIP levels are also present in PDAC patient plasma and supernatants of cultured PDAC cells. Furthermore, T cells up-regulate VIP receptors after activation, identifying the VIP signaling pathway as a potential target to enhance T cell function. In mouse PDAC models, VIP-R antagonist peptides synergize with anti-PD-1 antibody treatment in improving T cell recruitment into the tumors, activation of tumor-antigen-specific T cells, and inhibition of T cell exhaustion. In contrast to the limited single-agent activity of anti-PD1 antibodies or VIP-R antagonist peptides, combining both therapies eliminate tumors in up to 40% of animals. Furthermore, tumor-free mice resist tumor re-challenge, indicating anti-cancer immunological memory generation. VIP-R signaling thus represents a tumor-protective immune-modulatory pathway that is targetable in PDAC.

The neuropeptide VIP potentiates intestinal innate type 2 and type 3 immunity in response to feeding.

The nervous system and the immune system both rely on an extensive set of modalities to perceive and act on perturbations in the internal and external environments. During feeding, the intestine is exposed to nutrients that may contain noxious substances and pathogens. Here we show that Vasoactive Intestinal Peptide (VIP), produced by the nervous system in response to feeding, potentiates the production of effector cytokines by intestinal type 2 and type 3 innate lymphoid cells (ILC2s and ILC3s). Exposure to VIP alone leads to modest activation of ILCs, but strongly potentiates ILCs to concomitant or subsequent activation by the inducer cytokines IL-33 or IL-23, via mobilization of cAMP and energy by glycolysis. Consequently, VIP increases resistance to intestinal infection by the helminth Trichuris muris and the enterobacteria Citrobacter rodentium. These findings uncover a functional neuro-immune crosstalk unfolding during feeding that increases the reactivity of innate immunity necessary to face potential threats associated with food intake.

VIP plasma levels associate with survival in severe COVID-19 patients, correlating with protective effects in SARS-CoV-2-infected cells.

Infection by SARS‐CoV‐2 may elicit uncontrolled and damaging inflammatory responses. Thus, it is critical to identify compounds able to inhibit virus replication and thwart the inflammatory reaction. Here, we show that the plasma levels of the immunoregulatory neuropeptide VIP are elevated in patients with severe COVID‐19, correlating with reduced inflammatory mediators and with survival on those patients. In vitro, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase‐activating polypeptide (PACAP), highly similar neuropeptides, decreased the SARS‐CoV‐2 RNA content in human monocytes and viral production in lung epithelial cells, also reducing cell death. Both neuropeptides inhibited the production of proinflammatory mediators in lung epithelial cells and in monocytes. VIP and PACAP prevented in monocytes the SARS‐CoV‐2‐induced activation of NF‐kB and SREBP1 and SREBP2, transcriptions factors involved in proinflammatory reactions and lipid metabolism, respectively. They also promoted CREB activation, a transcription factor with antiapoptotic activity and negative regulator of NF‐kB. Specific inhibition of NF‐kB and SREBP1/2 reproduced the anti‐inflammatory, antiviral, and cell death protection effects of VIP and PACAP. Our results support further clinical investigations of these neuropeptides against COVID‐19.

Deletion of AMPA receptor GluA1 subunit gene (Gria1) causes circadian rhythm disruption and aberrant responses to environmental cues

Dysfunction of the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 subunit and deficits in synaptic plasticity are implicated in schizophrenia and sleep and circadian rhythm disruption. To investigate the role of GluA1 in circadian and sleep behaviour, we used wheel-running, passive-infrared, and video-based home-cage activity monitoring to assess daily rest–activity profiles of GluA1-knockout mice (Gria1−/−). We showed that these mice displayed various circadian abnormalities, including misaligned, fragmented, and more variable rest–activity patterns. In addition, they showed heightened, but transient, behavioural arousal to light→dark and dark→light transitions, as well as attenuated nocturnal-light-induced activity suppression (negative masking). In the hypothalamic suprachiasmatic nuclei (SCN), nocturnal-light-induced cFos signals (a molecular marker of neuronal activity in the preceding ~1–2 h) were attenuated, indicating reduced light sensitivity in the SCN. However, there was no change in the neuroanatomical distribution of expression levels of two neuropeptides―vasoactive intestinal peptide (VIP) and arginine vasopressin (AVP)―differentially expressed in the core (ventromedial) vs. shell (dorsolateral) SCN subregions and both are known to be important for neuronal synchronisation within the SCN and circadian rhythmicity. In the motor cortex (area M1/M2), there was increased inter-individual variability in cFos levels during the evening period, mirroring the increased inter-individual variability in locomotor activity under nocturnal light. Finally, in the spontaneous odour recognition task GluA1 knockouts’ short-term memory was impaired due to enhanced attention to the recently encountered familiar odour. These abnormalities due to altered AMPA-receptor-mediated signalling resemble and may contribute to sleep and circadian rhythm disruption and attentional deficits in different modalities in schizophrenia.

Vasoactive intestinal peptide promotes host defense against enteric pathogens by modulating the recruitment of group 3 innate lymphoid cells

Group 3 innate lymphoid cells (ILC3s) control the formation of intestinal lymphoid tissues and play key roles in intestinal defense. They express neuropeptide vasoactive intestinal peptide (VIP) receptor 2 (VPAC2), through which VIP modulates their function, but whether VIP exerts other effects on ILC3 remains unclear. We show that VIP promotes ILC3 recruitment to the intestine through VPAC1 independent of the microbiota or adaptive immunity. VIP is also required for postnatal formation of lymphoid tissues as well as the maintenance of local populations of retinoic acid (RA)-producing dendritic cells, with RA up-regulating gut-homing receptor CCR9 expression by ILC3s. Correspondingly, mice deficient in VIP or VPAC1 suffer a paucity of intestinal ILC3s along with impaired production of the cytokine IL-22, rendering them highly susceptible to the enteric pathogen Citrobacter rodentium This heightened susceptibility to C. rodentium infection was ameliorated by RA supplementation, adoptive transfer of ILC3s, or by recombinant IL-22. Thus, VIP regulates the recruitment of intestinal ILC3s and formation of postnatal intestinal lymphoid tissues, offering protection against enteric pathogens.

Гендерні аспекти впливу вазоінтестинального пептиду та інтерлейкіну-5 на показники екстракраніальної гемодинаміки в дітей із бронхіальною астмою

Актуальність. Огляд вітчизняної та зарубіжної науково-дослідної літератури свідчить, що на сьогодні системні наукові дослідження щодо взаємозв’язку між рівнем нейропептиду VIP (вазоактивний інтестинальний пептид — vasoactive intestinal peptide) та інтерлейкіну-5 у сироватці крові та станом мозкової гемодинаміки у хворих на бронхіальну астму дітей відсутні. Метою дослідження було встановити можливі впливи нейропептиду VIP та інтерлейкіну-5 на показники екстракраніальної гемодинаміки у хворих на бронхіальну астму дітей, проаналізувати гендерні особливості цих показників. Матеріали та методи. Проведено імунологічне дослідження сироватки крові для визначення рівня нейропептиду VIP та інтерлейкіну-5 у 54 хворих на бронхіальну астму дітей, серед яких були 21 дівчинка та 33 хлопчики віком 10–17 років. Контрольну групу становили 20 здорових дітей, які були ідентичні хворим за гендерним та віковим складом. Діти були обстежені двічі — при неконтрольованому та контрольованому перебігу хвороби. Також усім дітям проведено ультразвукове допплерографічне дослідження магістральних судин голови та шиї. Результати. Аналіз рівнів нейропептиду VIP та інтерлейкіну-5 установив гендерну залежність їх коливань: рівень нейропептиду VIP був статистично нижчим, а інтерлейкіну-5 — вищим у хворих хлопчиків із неконтрольованим перебігом бронхіальної астми порівняно із здоровими хлопчиками. У хворих із контрольованим перебігом бронхіальної астми негативний вплив на показники екстракраніальної гемодинаміки є мінімальним як у дівчаток, так й у хлопчиків. Висновки. Для здійснення дієвого контролю над перебігом захворювання потрібно враховувати зміни показників екстракраніальної гемодинаміки у хворих на бронхіальну астму дітей залежно від їх статі, що дозволить уникнути цереброваскулярних ускладнень у даного контингенту хворих.

Neurotransmitter serum levels in children with recurrent upper respiratory tract infections

Background. Schoolchildren are prone to frequent respiratory tract diseases. In the structure of general morbidity, this pathology ranks first. Its prevalence is more than 60 %, which leads to frequent school absenteeism, lack of active games and outdoor walks. So, there is an increase in the amount of time that a child spent on means of mass electronic communication and electronic games, resulting in high affection and addiction, forming hypodynamia, which in aggregate has a negative impact on the regulatory systems functioning. Recurrent upper respiratory tract infections (URTI) contribute to the strain of neuro-endocrine-immune regulation, causing an imbalance of neuropeptides — mediators of neurogenic inflammation. The purpose of this work is to study the neurogenic inflammation parameters in schoolchildren with functional disorders of the cardiovascular system and recurrent respiratory tract diseases. Materials and methods. We surveyed 130 children with URTI aged 6 to 9 years in the somatic well-being period. The analysis of the contents of vasoactive intestinal peptide (VIP), substance P and final stable metabolites of nitric oxide (FSM NO) in serum was carried out. An increase in substance P level in children with recurrent URTI was found, which had statistically significant differences with the healthy children indices (p &lt; 0.05). Results. It has been found that high concentration of substance P increases the risk of recurrent URTI. It has been proved that in children with recurrent URTI due to increased FSM NO serum content that has a pro-inflammatory orientation, there is an increased neurogenic inflammation activity. It was found that the reliable reduction in the content of VIP as an anti-inflammatory transmitter in children with recurrent URTI can not suppress the activity of neurogenic inflammation, resulting in its excessive stimulation. Conclusions. Children with recurrent URTI in the somatic well-being period have increased serum levels of substance Р and FSM NO. In the somatic well-being period in schoolchildren with recurrent URTI, a decrease in the concentration of anti-inflammatory neuropeptide VIP is observed.

The transcription factors SIX3 and VAX1 are required for suprachiasmatic nucleus circadian output and fertility in female mice.

The homeodomain transcription factors sine oculis homeobox 3 (Six3) and ventral anterior homeobox 1 (Vax1) are required for brain development. Their expression in specific brain areas is maintained in adulthood, where their functions are poorly understood. To identify the roles of Six3 and Vax1 in neurons, we conditionally deleted each gene using Synapsincre , a promoter targeting maturing neurons, and generated Six3syn and Vax1syn mice. Six3syn and Vax1syn females, but not males, had reduced fertility, due to impairment of the luteinizing hormone (LH) surge driving ovulation. In nocturnal rodents, the LH surge requires a precise timing signal from the brain's circadian pacemaker, the suprachiasmatic nucleus (SCN), near the time of activity onset. Indeed, both Six3syn and Vax1syn females had impaired rhythmic SCN output, which was associated with weakened Period 2 molecular clock function in both Six3syn and Vax1syn mice. These impairments were associated with a reduction of the SCN neuropeptide vasoactive intestinal peptide in Vax1syn mice and a modest weakening of SCN timekeeping function in both Six3syn and Vax1syn mice. Changes in SCN function were associated with mistimed peak PER2::LUC expression in the SCN and pituitary in both Six3syn and Vax1syn females. Interestingly, Six3syn ovaries presented reduced sensitivity to LH, causing reduced ovulation during superovulation. In conclusion, we have identified novel roles of the homeodomain transcription factors SIX3 and VAX1 in neurons, where they are required for proper molecular circadian clock function, SCN rhythmic output, and female fertility.

Attenuated serum vasoactive intestinal peptide concentrations are correlated with disease severity of non-traumatic osteonecrosis of femoral head

Background and objectiveThe neuropeptide vasoactive intestinal peptide is a 28-amino acid neuropeptide that has been shown to stimulate bone repair and angiogenesis. The purpose of this study was to explore the potential role of serum VIP concentration in osteonecrosis of femoral trauma (ONFH).MethodsOne hundred five patients diagnosed with non-traumatic ONFH and 103 healthy individuals were enrolled in our study. Serum VIP, tumor necrosis factor-α (TNF-α), interluekin-1 beta (IL-1β), and macrophage colony-stimulating factor (M-CSF) levels also were detected using the commercial ELISA kit. Radiographic progression was evaluated using FICAT classification. The clinical severity of ONFH was assessed by visual analog score (VAS) and Harris Hip Score (HHS). Receiver-operating characteristic (ROC) curve was performed to test the potential diagnostic value of VIP in radiographic progression.ResultsThe serum VIP level of patients with non-traumatic ONFH was significantly lower than that of healthy controls. There was no significant difference between the alcohol group, the steroid-induction group, and the idiopathic group. Serum VIP levels were significantly higher in ONFH patients with femoral head pre-collapse stage than collapse stage. Serum VIP levels were significantly lower. FICAT 4 non-traumatic ONFH patients had significantly lower serum concentrations of VIP when compared with FICAT 3 and FICAT 2. Moreover, serum VIP levels were significantly lower in ONFH patients with FICAT 3 than FICAT 2. Serum VIP levels were negatively related to FICAT stage. In addition, serum VIP levels were negatively associated with VAS score and positively associated with HHS score. Last, we found serum VIP levels were negatively associated with serum TNF-α and IL-1β levels. ROC curve analysis indicated that decreased serum VIP could serve as a decent biomarker with regard to the diagnosis of radiographic progression.ConclusionAttenuated serum VIP concentrations are correlated with disease severity of non-traumatic ONFH. Decreased serum VIP may serve as a potential indicator of non-traumatic ONFH.

Hedgehog signaling in endocrine and folliculo-stellate cells of the adult pituitary.

Ubiquitous overactivation of Hedgehog signaling in adult pituitaries results in increased expression of proopiomelanocortin (Pomc), growth hormone (Gh) and prolactin (Prl), elevated adrenocorticotropic hormone (Acth) production and proliferation of Sox2+ cells. Moreover, ACTH, GH and PRL-expressing human pituitary adenomas strongly express the Hedgehog target GLI1. Accordingly, Hedgehog signaling seems to play an important role in pathology and probably also in homeostasis of the adult hypophysis. However, the specific Hedgehog-responsive pituitary cell type has not yet been identified. We here investigated the Hedgehog pathway activation status and the effects of deregulated Hedgehog signaling cell-specifically in endocrine and non-endocrine pituitary cells. We demonstrate that Hedgehog signaling is unimportant for the homeostasis of corticotrophs, whereas it is active in subpopulations of somatotrophs and folliculo-stellate cells in vivo. Reinforcement of Hedgehog signaling activity in folliculo-stellate cells stimulates growth hormone production/release from somatotrophs in a paracrine manner, which most likely is mediated by the neuropeptide vasoactive intestinal peptide. Overall, our data show that Hedgehog signaling affects the homeostasis of pituitary hormone production via folliculo-stellate cell-mediated regulation of growth hormone production/secretion.

The Cell-Autonomous Clock of VIP Receptor VPAC2 Cells Regulates Period and Coherence of Circadian Behavior.

Circadian (approximately daily) rhythms pervade mammalian behavior. They are generated by cell-autonomous, transcriptional/translational feedback loops (TTFLs), active in all tissues. This distributed clock network is coordinated by the principal circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN). Its robust and accurate time-keeping arises from circuit-level interactions that bind its individual cellular clocks into a coherent time-keeper. Cells that express the neuropeptide vasoactive intestinal peptide (VIP) mediate retinal entrainment of the SCN; and in the absence of VIP, or its cognate receptor VPAC2, circadian behavior is compromised because SCN cells cannot synchronize. The contributions to pace-making of other cell types, including VPAC2-expressing target cells of VIP, are, however, not understood. We therefore used intersectional genetics to manipulate the cell-autonomous TTFLs of VPAC2-expressing cells. Measuring circadian behavioral and SCN rhythmicity in these temporally chimeric male mice thus enabled us to determine the contribution of VPAC2-expressing cells (∼35% of SCN cells) to SCN time-keeping. Lengthening of the intrinsic TTFL period of VPAC2 cells by deletion of the CK1εTau allele concomitantly lengthened the period of circadian behavioral rhythms. It also increased the variability of the circadian period of bioluminescent TTFL rhythms in SCN slices recorded ex vivo Abrogation of circadian competence in VPAC2 cells by deletion of Bmal1 severely disrupted circadian behavioral rhythms and compromised TTFL time-keeping in the corresponding SCN slices. Thus, VPAC2-expressing cells are a distinct, functionally powerful subset of the SCN circuit, contributing to computation of ensemble period and maintenance of circadian robustness. These findings extend our understanding of SCN circuit topology.

The neuropeptide VIP confers anticipatory mucosal immunity by regulating ILC3 activity.

Group 3 innate lymphoid cell (ILC3)-mediated production of the cytokine interleukin-22 (IL-22) is critical for the maintenance of immune homeostasis in the gastrointestinal tract. Here, we find that the function of ILC3s is not constant across the day, but instead oscillates between active phases and resting phases. Coordinate responsiveness of ILC3s in the intestine depended on the food-induced expression of the neuropeptide vasoactive intestinal peptide (VIP). Intestinal ILC3s had high expression of the G protein-coupled receptor vasoactive intestinal peptide receptor 2 (VIPR2), and activation by VIP markedly enhanced the production of IL-22 and the barrier function of the epithelium. Conversely, deficiency in signaling through VIPR2 led to impaired production of IL-22 by ILC3s and increased susceptibility to inflammation-induced gut injury. Thus, intrinsic cellular rhythms acted in synergy with the cyclic patterns of food intake to drive the production of IL-22 and synchronize protection of the intestinal epithelium through a VIP-VIPR2 pathway in ILC3s.

The Neuropeptide Vasoactive Intestinal Peptide Levels in Serum are Inversely Related to Disease Severity of Postmenopausal Osteoporosis: A Cross-Sectional Study.

Background: The neuropeptide vasoactive intestinal peptide (VIP) has been identified as inhibiting osteoclastogenesis and suppressing inflammation. Objective: This study was conducted to examine serum VIP levels in postmenopausal osteoporosis (PMOP) patients and explore the correlation of serum VIP levels with disease severity of PMOP. Methods: A total of 106 postmenopausal women diagnosed as osteoporotic were enrolled in the study and 102 postmenopausal women with normal bone mineral density (BMD) were enrolled as controls. BMD at the femoral neck (FN), lumbar spine 1-4, and total hip were examined using dual-energy X-ray absorptiometry. Genant semiquantitative grading was used for vertebral morphometry and fracture. Serum VIP levels were tested using enzyme-linked immunosorbent assay. Serum inflammatory factor interleukin-1β (IL-1β), osteoclastic activity marker tartrate-resistant acid phosphatase 5b (TRACP-5b), and estrogen-2 (E2) were also examined. Receiver operating characteristic (ROC) analyses was performed to determine the diagnostic values of serum VIP, IL-1β, TRCAP-5, and E2 with regard to Genant grade. Results: Our findings demonstrated a reduction in the serum level of VIP expressed in PMOP patients compared with controls. In the PMOP group, patients with lumbar fracture had significantly lower serum VIP concentrations in comparison with healthy controls. Serum VIP concentrations were positively associated with BMD at the FN, lumbar spine 1-4, and total hip. We also observed that serum VIP levels were positively correlated with E2 levels but negatively correlated with IL-1β and TRCAP-5 levels. In addition, ROC analysis found that reduction of serum VIP in combination with elevation of TRACP-5b may serve as an indicator of a severe Genant grade. Conclusions: Attenuated serum VIP levels were linked to disease severity of PMOP and may act as a protective marker for PMOP.