Role Of Vasoactive Intestinal Peptide Research Articles

The effect of active immunization against vasoactive intestinal peptide (VIP) and inhibin on reproductive performance of aging White Leghorn roosters

Decreasing fertility in aging domestic roosters is a well-known phenomenon. Aging is manifested by a decrease in plasma testosterone level, testis function, and spermatogenesis, resulting in a low level of fertility. The roles of vasoactive intestinal peptide (VIP) and testicular inhibin in this aging process are not clear. The effects of active immunization against VIP, inhibin, or the combination of both hormones on the reproduction of aging White Leghorn (WL) roosters were assayed. In experiment 1a, 60 White Leghorn roosters (67 wk of age) were divided into 4 groups (n = 15/group). The first group was actively immunized against VIP, the second against inhibin, the third against VIP and inhibin, and the fourth served as a control. Active immunization against VIP decreased semen quality parameters, plasma steroid levels, and gene expression of gonadotropin-releasing hormone-I (GnRH-I), follicle-stimulating hormone (FSH), luteinizing hormone (LH), LH receptor, VIP, and prolactin (Prl). Immunization against inhibin increased some of the semen quality parameters and FSH mRNA gene expression but decreased inhibin gene expression. In experiment 1b, at 94 wk of age, we took the actively immunized against VIP group and the control group and divided them into 2 subgroups (n = 7 or 8): the first group was injected with 1 mg of ovine Prl (oPrl) daily for 7 d, and the second group served as a control. Administration of oPrl to previously VIP-immunized birds significantly elevated semen quality parameters. We suggest that VIP, Prl, and inhibin have an important effect on the reproductive axis in aging roosters. Active immunization against VIP-depressed reproductive activity and Prl administration restored their reproduction, indicating that both VIP and Prl are essential for reproduction in aging roosters. Immunization against inhibin improved FSH mRNA gene expression, suggesting a negative role of inhibin on FSH secretion in aging roosters. Not all semen quality parameters increased significantly after immunization against inhibin, even though FSH mRNA gene expression increased, suggesting interference in testicular function in aging roosters.

Circadian regulation of cardiovascular function: a role for vasoactive intestinal peptide

The circadian system, driven by the suprachiasmatic nucleus (SCN), regulates properties of cardiovascular function. The dysfunction of this timing system can result in cardiac pathology. The neuropeptide vasoactive intestinal peptide (VIP) is crucial for circadian rhythms in a number of biological processes including SCN electrical activity and wheel running behavior. Anatomic evidence indicates that SCN neurons expressing VIP are well positioned to drive circadian regulation of cardiac function through interactions with the autonomic centers. In this study, we tested the hypothesis that loss of VIP would result in circadian deficits in heart rate (HR) and clock gene expression in cardiac tissue. We implanted radiotelemetry devices into VIP-deficient mice and wild-type (WT) controls and continuously recorded HR, body temperature, and cage activity in freely moving mice. Under light-dark conditions, VIP-deficient mice displayed weak rhythms in HR, body temperature, and cage activity, with onsets that were advanced in phase compared with WT mice. Similarly, clock gene expression in cardiac tissue was rhythmic but phase advanced in mutant mice. In constant darkness, the normal circadian rhythms in HR were lost in VIP-deficient mice; however, most mutant mice continued to exhibit circadian rhythms of body temperature with shortened free-running period. The loss of VIP altered, but did not abolish, autonomic regulation of HR. Analysis of the echocardiograms did not find any evidence for a loss of cardiac function in VIP-deficient mice, and the size of the hearts did not differ between genotypes. These results demonstrate that VIP is an important regulator of physiological circadian rhythmicity in the heart.

Role of Vasoactive Intestinal Peptide in Hyperoxia-Induced Injury of Primary Type II Alveolar Epithelial Cells

We investigated the effect of VIP on primary type II alveolar epithelial cells (AECIIs) upon the exposure of hyperoxia. AECIIs were isolated and purified from premature rats and exposed to air (21% oxygen), hyperoxia(95% oxygen), VIP+air and VIP+hyperoxia, respectively. The proliferation and apoptosis of AECIIs were detected by MTT cell proliferation assay, flow cytometry and western blot. The production of intracellular reactive oxygen species (ROS) was determined by 2 ', 7'-dichloro-dihydrotestosterone fluorescein diacetate (DCFH-DA) molecular probe and the total antioxidant capacity (TAOC) by ultraviolate spectro-photometer. Cell proliferation significantly increased and apoptosis decreased upon the treatment with VIP. In addition, the level of ROS in the hyperoxia+VIP group was significantly lower than in the hyperoxia group, in contrast, TAOC was higher in the hyperoxia+VIP group than that in the hyperoxia group. VIP exerts a protective role in the hyperoxia-induced oxidative stress damage in AECIIs, which probably attributed to its anti-oxidant and anti-apoptosis property.

Inhaled Vasoactive Intestinal Peptide Exerts Immunoregulatory Effects in Sarcoidosis

Previous studies suggest an important immunoregulatory role of vasoactive intestinal peptide (VIP) in experimental models of chronic noninfectious inflammation. Sarcoidosis is characterized by noncaseating epitheloid cell granulomas, where excessive tumor necrosis factor-alpha production by pulmonary macrophages plays a critical role in granuloma formation and disease progression, which may lead to fatal organ dysfunction. To test whether inhaled VIP has an immunoregulatory role. Sarcoid alveolitis was used as a prototype of immune-mediated chronic lung inflammation. In an open clinical phase II study, we treated 20 patients with histologically proved sarcoidosis and active disease with nebulized VIP for 4 weeks. VIP inhalation was safe, well-tolerated, and significantly reduced the production of tumor necrosis factor-alpha by cells isolated from bronchoalveolar lavage fluids of these patients. VIP treatment significantly increased the numbers of bronchoalveolar lavage CD4(+)CD127(-)CD25(+) T cells, which showed regulatory activities on conventional effector T cells. In vitro experiments demonstrated the capacity of VIP to convert naive CD4(+)CD25(-) T cells into CD4(+)CD25(+)FoxP3(+) regulatory T cells, suggesting the generation of peripheral regulatory T cells by VIP treatment. This study is the first to show the immunoregulatory effect of VIP in humans, and supports the notion of inhaled VIP as an attractive future therapy to dampen exaggerated immune responses in lung disorders. Thus, the inhalation of neuropeptides may be developed into a new therapeutic principle for chronic inflammatory lung disorders in humans.

New insights into the role of VIP on the ratio of T‐cell subsets during the development of autoimmune diabetes

Type I diabetes is an autoimmune T-cell-mediated disease associated with overexpression of inflammatory mediators and the disturbance of different T-cell subsets. Vasoactive intestinal peptide (VIP) is a potent anti-inflammatory agent with regulatory effects on activated T cells. As the equilibrium between different T-cell subsets is involved in the final outcome, leading to tolerance or autoimmunity, we studied the evolution of markers for T cells in nonobese diabetic (NOD) mice. The study of different transcription factors, cytokines or cytokine receptors, shows that VIP interferes with functional phase of T helper 17 (Th17) cells and prevents the increase in the proportion of Th1 to Th17 cells. On the other hand, VIP-treated NOD mice show an increase in the proportion of CD4(+)CD25(+) cells in the spleen. Thus, VIP switches the Tregs/Th17 ratio leading to tolerance in NOD mice. Similarly, VIP reverses the ratio of Th1-/Th2-cell subsets associated with autoimmune pathology. All these effects on the ratio of T-cell subsets and the anti-inflammatory effect of VIP in decreasing proinflammatory mediators result in a reduction of β-cell destruction in pancreas. Taken together, these results show that VIP provides significant protection against spontaneous diabetes by modulating T-cell subsets and counterbalancing tolerance and immunity.

Immunomodulation of innate immune responses by vasoactive intestinal peptide (VIP): its therapeutic potential in inflammatory disease

Since the late 1970s a number of laboratories have studied the role of vasoactive intestinal peptide (VIP) in inflammation and immunity. These studies have highlighted the dramatic effect of VIP on immune cell activation and function, and studies using animal models of disease have indicated that VIP has significant therapeutic and prophylactic potential. This review will focus on the effects of VIP on innate immune cell function and discuss the therapeutic potential for VIP in inflammatory diseases of humans.

Vasoactive intestinal peptide acts via multiple signal pathways to regulate hippocampal NMDA receptors and synaptic transmission

Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide, which belongs to a superfamily of structurally related peptide hormones including pituitary adenylate cyclase-activating polypeptide (PACAP). Although several studies have identified the involvement of PACAP in learning and memory, little work has been done to investigate such a role for VIP. At least three receptors for VIP have been identified including the PACAP receptor (PAC1-R) and the two VIP receptors (VPAC receptors). VIP can activate the PAC1-R only if it is used at relatively high concentrations (e.g., 100 nM); however, at lower concentrations (e.g., 1 nM) it is selective for the VPAC receptors. Our lab has showed that PAC1-R activation signals through PKC/CAKbeta/Src pathway to regulate NMDA receptors; however, there is little known about the potential regulation of NMDA receptors by VPAC receptors. Our studies demonstrated that application of 1 nM VIP enhanced NMDA currents by stimulating the VPAC receptors as the effect was blocked by VPAC receptor antagonist [Ac-Tyr(1), D-Phe(2)]GRF (1-29). This enhancement of NMDA currents was blocked by both Rp-cAMPS and PKI(14-22) (they are highly specific PKA inhibitors), but not by the specific PKC inhibitor, bisindolylmaleimide I. In addition, the VIP-induced enhancement of NMDA currents was accentuated by inhibition of phosphodiesterase 4, which inhibits the degradation of cAMP. This regulation of NMDA receptors also required the scaffolding protein AKAP. In contrast, the potentiation induced by high concentration of VIP (e.g., 100 nM) was mediated by PAC1-R as well as by Src kinase. Overall, these results show that VIP can regulate NMDA receptors through different receptors and signaling pathways.

The Role of Vasoactive Intestinal Peptide (VIP) in Megakaryocyte Proliferation

Megakaryocytopoiesis is a multistage process that involves differentiation of hematopoietic stem cells through the myeloid lineage, ultimately producing megakaryocytes and platelets. Vasoactive intestinal peptide (VIP) stimulates adenylate cyclase and induces differentiation in multiple cell types; VIP is expressed in hematopoietic stem cells and in megakaryocytes, but its function in these cells has not yet been delineated. The present study was designed to investigate whether the type 1 VIP receptor, VPAC1, mediates VIP effects on megakaryocytopoiesis. The human megakaryoblastic leukemia cell line (CMK) was transfected with VPAC1 and the transgene expression was confirmed by qualitative polymerase chain reaction and immunohistochemistry. The rate of proliferation and the patterns of differentiation were then compared for CMK and CMK/VPAC1 through multiple growth cycles. Upregulation of VPAC1 expression resulted in a decreased proliferation rate (p = 0.0003) and enhanced differentiation with CMK/VPAC1 cells having twice the cell surface area of control CMK cells (p = 0.001), thus increasing potential for proplatelet formation. These results suggest that VIP acts in an autocrine fashion via VPAC1 to inhibit megakaryocyte proliferation and induce proplatelet formation.

Vasoactive Intestinal Peptide Is Critical for Circadian Regulation of Glucocorticoids

Background/Aims: Circadian control of behavior and physiology is a central characteristic of all living organisms. The master clock in mammals resides in the hypothalamus, where the suprachiasmatic nucleus (SCN) synchronizes daily rhythms. A variety of recent evidence indicates that the neuropeptide vasoactive intestinal peptide (VIP) is critical for normal functioning of the SCN. The aim of our study was to examine the possible role of VIP in driving circadian rhythms in the hypothalamic-pituitary-adrenal axis. Methods: Circulating ACTH and corticosterone concentrations were determined by round-the-clock sampling under diurnal and circadian conditions. The responsive aspects of the hypothalamic-pituitary-adrenal axis were tested by application of acute stress by footshock and light. Results: We demonstrate that the circadian rhythms in ACTH and corticosterone are lost in VIP-deficient mice. The ability of light to induce a corticosterone response was also compromised in the mutant mice, as was photic induction of Per1 in the adrenal glands. In contrast, the acute stress response was apparently unaltered by the loss of VIP. Conclusion: Thus, our data demonstrate that VIP is essential for the circadian regulation of an otherwise intact hypothalamic-pituitary-adrenal axis.

Role of vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide in the vaginal wall of women with stress urinary incontinence and pelvic organ prolapse

Pelvic floor connective tissue degeneration is closely associated with retrogradation of its dominating nerve fibers. We hypothesized that some neuropeptides from pelvic floor tissue might be involved in the pathological progress of stress urinary incontinence (SUI) and pelvic organ prolapse (POP) in women. Thirty premenopausal and 31 postmenopausal patients participated in the study. The morphological appearance in the vaginal tissue was examined. The vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide-38 (PACAP) immunoreactivities (ir-VIP, ir-PACAP) were tested by immunohistochemistry and radioimmunoassay. We found that the VIP and PACAP immunostainings were weaker and sparser, and ir-VIP and ir-PACAP levels were significantly decreased in the anterior vaginal wall in the premenopausal and postmenopausal SUI or POP patients. Ir-VIP and ir-PACAP levels were reversely correlated with the age and menopausal status in the SUI or POP patients. Our data suggest that VIP and PACAP may participate in the pathophysiological process of SUI and POP.

Emerging roles of vasoactive intestinal peptide: a new approach for autoimmune therapy

Identification of the factors that regulate the immune tolerance and control the appearance of exacerbated inflammatory conditions is crucial for the development of new therapies of autoimmune diseases. Some neuropeptides...

The role of vasoactive intestinal peptide in neuroprotection: interview with Professor Illana Gozes

Professor Illana Gozes was interviewed by Emma Quigley (Senior Editor, Expert Opinion) on 17th April 2007.Professor Illana Gozes BSc, PhD holds the titles of Professor of Clinical Biochemistry; The Lily and Avraham Gildor Chair for the Investigation of Growth Factors; Director of Adams Super Center for Brain Studies and Levi-Edersheim-Gitter fMRI Institute; Head of the Dr Diana and Zelman Elton (Elbaum) Laboratory for Molecular Neuroendocrinology, Tel Aviv University and Chief Scientific Officer, Allon Therapeutics, Inc., Vancouver BC, Canada. Professor Gozes has served as a member (or chair) of several faculty, university or national and international committees and she currently serves on the Board of Directors of Allon Therapeutics, the Scientific Review Board of the ISOA, and is the Editor-in-Chief of the Journal of Molecular Neuroscience. Professor Gozes has received a number of scientific awards for her work including the Landau Award for an excellent PhD dissertation, the Juludan Prize and the Teva Founders Prize for exceptional scientific studies that may lead to biotechnology developments as well as the Bergmann Prize and the Neufeld award for outstanding/leading US-Israel BSF grant proposals, and has published extensively in the fields of molecular neuroscience and neuroprotection (> 200 scientific manuscripts). She is co-inventor of > 15 patents and applications, including the composition of matter patent on AL-108 and AL-208, Allon's lead compounds. Professor Gozes received a BSc from Tel Aviv University, a PhD from The Weizmann Institute of Science and was a Weizmann Postdoctoral Fellow at Massachusetts Institute of Technology, Research Associate/Visiting Scientist at the Salk Institute and the Scripps Clinic and Research Foundation, a Senior Scientist/Associate Professor at the Weizmann Institute and a Fogarty-Scholar-in-Residence at the National Institutes of Health (USA). Professor Gozes directs a very active research laboratory at Tel Aviv University and is mentoring and has mentored directly ∼ 50 graduate students toward their MSc or PhD degrees.

Vasoactive intestinal peptide, periodontal disease, and the innate immune response: an interview with Dr. John J. Taylor.

Vasoactive intestinal peptide, periodontal disease, and the innate immune response: an interview with Dr. John J. Taylor.

Mechanisms of vasoactive intestinal peptide-elicited coronary vasodilation in the isolated perfused rat heart

The present study investigated the potential role of vasoactive intestinal peptide (VIP) receptors, VPAC1 and VPAC2, in VIP-elicited coronary vasodilation of the isolated perfused rat heart. Additional studies determined the role of ATP-sensitive (K(ATP)) and voltage-gated K(+) (K(V)) channels in the VIP-elicited coronary vasodilation. Both the selective VPAC1 agonist, K15,R16,L27VIPl-7GRF8-27, and the selective VPAC2 agonist, RO25-1553, decreased coronary vascular resistance (CVR) in a dose-dependent manner, with EC(50) values of 1.67x10(-9)M and 7.11x10(-9)M, respectively (VPAC1 vs VPAC2 agonist, P<0.05). K15,R16,L27VIP1-7GRF8-27 and RO25-1553 maximally reduced CVR by -42+/-4% and -39+/-6% at 1x10(-8) and 3x10(-8)M, respectively. VIP at 1x10(-10)M decreased CVR by -14+/-2% in the absence (vehicle), by -11+/-3% in the presence of the nonselective VIP receptor antagonist VIP10-28 (1x10(-7)M; P>0.05 vs. vehicle) and by only -4+/-2% in the presence of the selective VPAC2 receptor antagonist PACAP6-38 (1x10(-7)M; P<0.05 vs. vehicle). In additional studies, VIP at 1x10(-10)M decreased CVR by -22+/-1% in the absence (control) and by only -10+/-2% in the presence of the nonselective K(+) channel blocker tetrabutylammonium (3x10(-4)M; P<0.05 vs. control). VIP reduced CVR by -4+/-1% in the presence of the K(ATP) channel blocker glibenclamide (3x10(-6)M; P<0.05 vs control) and by -28+/-2% in the presence of the K(V) channel blocker 4-aminopyridine (3x10(-4)M; P>0.05 vs control). Thus, selective VPAC1 and VPAC2 receptor activation in the coronary circulation produces vasodilation and the VIP-elicited coronary vasodilation involves activation of VPAC2 receptors and K(ATP) but not K(V) channels. In addition, VIP10-28 does not effectively block coronary vascular VIP receptors.

Role of vasoactive intestinal peptide and nitric oxide in the modulation of electroacupucture on gastric motility in stressed rats

To investigate the effects and mechanisms of vasoactive intestinal peptide (VIP) and nitric oxide (NO) in the modulation of electroacupucture (EA) on gastric motility in restrained-cold stressed rats. An animal model of gastric motility disorder was established by restrained-cold stress. Gastric myoelectric activities were recorded by electrogastroenterography (EGG). VIP and NO concentrations in plasma and gastric mucosal and bulb tissues were detected by radioimmunoassay (RIA). VIP expression in the gastric walls was assayed using avidin-biotin-peroxidase complex (ABC) and image analysis. In cold restrained stressed rats, EGG was disordered and irregular. The frequency and amplitude of gastric motility were higher than that in control group (P < 0.01). VIP and NO contents of plasma, gastric mucosal and bulb tissues were obviously decreased (P < 0.01). Following EA at "Zusanli" (ST36), the frequency and amplitude of gastric motility were obviously lowered (P < 0.01), while the levels of VIP and NO in plasma, gastric mucosal and bulb tissues increased strikingly (P < 0.01, P < 0.05) and expression of VIP in antral smooth muscle was elevated significantly (P < 0.01) in comparison with those of model group. VIP and NO participate in the modulatory effect of EA on gastric motility. EA at "Zusanli" acupoint (ST36) can improve gastric motility of the stressed rats by increasing the levels of VIP and NO.

Placental Expression of Substance P and Vasoactive Intestinal Peptide: Evidence for a Local Effect on Hormone Release

The present study evaluated vasoactive intestinal peptide (VIP) and substance P (SP) mRNA expressions and the localization of both peptides in first- and third-trimester human placentas. VIP and SP mRNAs were detected by slot blot analysis in first- and third-trimester placental tissues. By immunohistochemistry both neuropeptides were localized in the trophoblast (syncytium and cytotrophoblastic cells) of the chorionic villi. Because little information is available on the role of VIP and/or SP on the secretion of placental hormones, we investigated the effect of these neuropeptides on human chorionic gonadotropin (hCG) and progesterone release from primary cultured human trophoblastic and JEG-3 cells. The addition of increasing doses of VIP resulted in a dose-dependent stimulation of hCG release from cultured human trophoblast and JEG-3 cells. Increasing doses of VIP also dose-dependently stimulated progesterone secretion from primary cultured trophoblastic cells at all time points evaluated and from JEG-3 cells only after 3 h. SP did not affect hCG and progesterone secretion either in cultured human trophoblast or in JEG-3 cells. In conclusion, the present study demonstrates that VIP and SP are mainly expressed in human trophoblasts, and that VIP modulates the in vitro secretion of hCG and progesterone, suggesting a different role in trophoblastic function of the two peptides.

Coronary vascular effects of vasoactive intestinal peptide in the isolated perfused rat heart.

The potency and mechanism of action of vasoactive intestinal peptide (VIP) for producing coronary vasodilation was investigated in the isolated perfused heart of the rat. VIP reduced coronary vascular resistance in a dose-dependent manner, starting at 1 x 10(-10) M, and maximally reduced coronary vascular resistance by 49% at 1 x 10(-8) M. The potency of VIP for reducing coronary vascular resistance (EC50=3.02 x 10(-10) M) was considerably greater than that of adenosine (EC50=6.17 x 10(-8) M) and sodium nitroprusside (EC50=2.45 x 10(-6) M). The vasodilatory action of VIP was more easily observed after increasing vascular tone by perfusion of the hearts with a modified physiological solution containing reduced concentrations of potassium (3.2 mM) and calcium (1.2 mM). Under these conditions, VIP maximally reduced coronary resistance by 54% at 7 x 10(-9) M. The potency of VIP for reducing coronary resistance in these hearts, however, decreased 16-fold (EC50=4.90 x 10(-9) M) while that of SNP remained unaltered (EC50=3.39 x 10(-6) M), compared with hearts perfused with higher levels of potassium (5.9 mM) and calcium (2.5 mM). The vasodilatory effect of VIP occurred without a significant change in heart rate, myocardial contractility or oxygen consumption. In additional studies, the dose-dependent effect of VIP on cyclic nucleotide release from the heart was determined by infusing VIP into the coronary circulation in a cumulative fashion to produce final concentrations between 1 x 10(-11) and 1 x 10(-9) M. VIP increased cyclic AMP at 1 x 10(-9) M but did not increase cyclic GMP. Studies using RT-PCR and immunohistochemistry clearly demonstrated the presence of two VIP receptor subtypes, VPAC1 and VPAC2, in the arteries and arterioles of the heart. In conclusion, VIP is a potent vasodilator in the coronary circulation of the rat and the role of VIP in the control of coronary vascular resistance depends on the circulating levels of potassium and calcium. This vasodilatory effect involves binding to specific coronary cell surface receptors, VPAC1 and/or VPAC2, and is dependent on cyclic AMP only during maximal vasodilation.

A Role for Histamine in Active Vasodilation

0267 It has been established that nitric oxide (NO) is involved in cutaneous active vasodilation. Recent evidence suggests vasoactive intestinal peptide (VIP) may be involved in active vasodilation and we have recently shown that VIP-mediated dilation includes a substantial NO-dependent portion. Furthermore, VIP has been shown to induce histamine release from mast cells in human skin. Thus, it is possible that the NO portion of active vasodilation may be due to release of histamine. PURPOSE: To determine the relative contribution of NO and histamine during whole body heating. METHODS: Six subjects were instrumented with 4 microdialysis fibers. Site 1 served as a control and was infused with Ringer's solution. Site 2 received 10 mM L-NAME to inhibit NO synthase (NOS). Site 3 received the H1 receptor antagonist pyrilamine maleate (500 μM). Site 4 was infused with L-NAME combined with H1 receptor antagonist (final concentrations of 10 mM and 500 μM). All infusions were continuous beginning 30 minutes prior to whole body heating and throughout the duration of the heating period. Subjects wore a water-perfused suit and hot water was pumped through the suit to increase core temperature at least 0.8°C. Laser-Doppler flowmetery was used to monitor skin blood flow (SkBF) over each site. Cutaneous vascular conductance (CVC) was calculated as flux/mean arterial pressure and normalized to maximal values via infusion of 28 mM sodium nitroprusside. RESULTS: In control sites, CVC increased during whole body heating to 69±3 %CVCmax. CVC values were significantly reduced in sites receiving NOS inhibition (32±2 %CVCmax; p<0.001) and in sites receiving H1 antagonist only (51±3 %CVCmax; p<0.05). CVC in sites that received NOS inhibition combined with H1 antagonist was attenuated compared to control (33±3 %CVCmax; p<0.001). However, there was no difference between NOS inhibited sites and combined NOS inhibitor and H1 antagonist sites. Additionally, NOS inhibited sites and combined NOS inhibitor and H1 antagonist sites were significantly reduced compared to H1 antagonist only sites (p<0.05). CONCLUSION: The increase in SkBF during whole body heating contains both a histamine component. Furthermore, these data are consistent with a role for VIP in active vasodilation. Supported by NIH Grant HL 70928

Role of vasoactive intestinal peptide and inflammatory mediators in enteric neuronal plasticity.

Complex circuits involving both local intrinsic neurones (i.e. enteric nervous system; ENS) and extrinsic neurones achieve nervous control of digestive functions. The ENS is comprised of many functionally different types of neurons: sensory neurons, interneurons and secreto-motor neurons. Each neuronal population is required to manifest local reflex behavior and is central to the regulation of both motor and secretory activities. It must be emphasized, however, that not only muscle and secretory cells but also other intestinal cells are targeted by enteric neurones, i.e. endocrine cells, interstitial cells of Cajal, immune cells, blood vessels and enteric glia. In addition to the ENS the gastrointestinal tract receives an extrinsic innervation by sympathetic, parasympathetic and sensory fibres. Neuronal projections from the intestine to prevertebral ganglia also exist. Taken together, the picture of a complex nervous regulation of digestive functions highly integrated with the central nervous system and the rest of the autonomic nervous system has emerged. The ENS is adaptive and plastic, but also vulnerable, system and ENS disturbances may be of pathogenic importance in functional bowel disease. In particular the interplay between the enteric neurones and the immune cells is suggested to be of crucial importance. The review discusses possible roles of the mediators vasoactive intestinal peptide (VIP) and prostanoids in ENS plasticity in response to injury and inflammation.

Preferential expression of the vasoactive intestinal peptide (VIP) receptor VPAC1 in human cord blood-derived CD34+CD38- cells: possible role of VIP as a growth-promoting factor for hematopoietic stem/progenitor cells.

Primitive hematopoietic progenitor cells such as severe combined immunodeficiency- repopulating cells and long-term culture-initiating cells are enriched in CD34+CD38- cells derived from various stem cell sources. In this study, to elucidate the features of such primitive cells at the molecular level, we tried to isolate genes that were preferentially expressed in umbilical cord blood (CB)-derived CD34+CD38- cells by subtractive hybridization. The gene for VPAC1 receptor, a receptor for the neuropeptide vasoactive intestinal peptide (VIP), was thereby isolated and it was shown that this gene was expressed in both CD34+CD38- and CD34+CD38+ CB cells and that the expression levels were higher in CD34+CD38- CB cells. Next, we assessed the effects of VIP on the proliferation of CD34+ CB cells using in vitro culture systems. In serum-free single-cell suspension culture, VIP enhanced clonal growth of CD34+ CB cells in synergy with FLT3 ligand (FL), stem cell factor (SCF), and thrombopoietin (TPO). In serum-free clonogenic assays, VIP promoted myeloid (colony-forming unit-granulocyte/macrophage (CFU-GM)) and mixed (CFU-Mix) colony formations. Furthermore, in Dexter-type long-term cultures, VIP increased colony-forming cells at week 5 of culture. These results suggest that VIP functions as a growth-promoting factor of CB-derived hematopoetic progenitor cells.