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Vasoactive intestinal peptide

Vasoactive intestinal peptide (VIP) is a 28-amino-acid neuropeptide that acts as both a neurotransmitter and a hormone, belonging to the secretin/glucagon superfamily and renowned for its potent vasodilatory properties.^[1]^[2] First isolated from porcine duodenum extracts in 1970 by Sami I. Said and Viktor Mutt, VIP was named for its ability to induce peripheral and splanchnic vasodilation, initially identified as a polypeptide with broad biological activity.^[3] The peptide features an amidated C-terminus and is derived from a prepro-VIP precursor encoded by a gene on human chromosome 6q24.^[1] VIP is ubiquitously distributed throughout the body, with high concentrations in the central and peripheral nervous systems, particularly in the gastrointestinal (GI) tract where it is localized in myenteric and submucosal neurons.^[1] It is also expressed in various immune cells, including T lymphocytes and mast cells, as well as in reproductive, respiratory, and cardiovascular tissues.^[1] This widespread presence underscores its role in diverse physiological processes beyond the GI system.^[4] Physiologically, VIP exerts multiple effects, including relaxation of smooth muscle in the GI tract and airways, stimulation of epithelial ion secretion and nutrient absorption, and inhibition of gastric acid secretion to regulate GI motility and homeostasis.^[1] In the cardiovascular system, it promotes vasodilation, lowers arterial blood pressure, enhances coronary blood flow, and increases cardiac contractility while exhibiting anti-hypertrophic properties on cardiomyocytes.^[4] Additionally, VIP modulates immune responses by suppressing pro-inflammatory cytokines like TNF-α, supports glycemic control through glucose-dependent insulin secretion, and provides neuroprotection in the central nervous system.^[1]^[5] VIP primarily signals through two class B G-protein-coupled receptors: VPAC1, which is expressed on epithelial cells and immune cells to mediate secretory and immunomodulatory effects, and VPAC2, predominant on smooth muscle and pancreatic β-cells to influence motility and insulin release.^[1] These receptors couple to Gs proteins, activating adenylyl cyclase to increase cyclic AMP levels, though VPAC1 can also engage other pathways like phospholipase C.^[6] Due to its pleiotropic actions, VIP and its analogs are under investigation for therapeutic applications in conditions such as inflammatory bowel disease, diabetes, pulmonary hypertension, and neurodegenerative disorders, despite challenges posed by its short half-life from rapid enzymatic degradation.^[1]^[5]

Discovery and Structure

Discovery

Vasoactive intestinal peptide (VIP) was first identified in 1970 by Sami I. Said and Viktor Mutt during their search for vasodilatory substances in gastrointestinal tissues.^[3] The researchers had previously reported a vasodilatory peptide fraction from porcine lung tissue in 1969, prompting them to shift their focus to porcine duodenal extracts where they successfully purified a potent vasodilator.^[7] This new peptide exhibited broad biological activity, including marked hypotension and increased splanchnic blood flow upon intravenous administration in anesthetized dogs, distinguishing it as a novel entity. Due to its striking vasodilatory effects and intestinal origin, the peptide was named vasoactive intestinal peptide, though early observations noted similarities to secretin in stimulating pancreatic bicarbonate secretion and intestinal smooth muscle relaxation, leading to initial confusion about its identity.^[1] Said and Mutt's team conducted key experiments demonstrating these properties: in vivo assays showed dose-dependent vasodilation without significant cardiac stimulation, while in vitro studies on isolated gut preparations confirmed secretory enhancement and inhibitory effects on smooth muscle tone.^[3] These findings highlighted VIP's potential as a physiological regulator in the gut and vasculature. Further purification efforts through chromatography and bioassays confirmed VIP as a distinct peptide separate from secretin and other known gut hormones. By 1974, detailed structural analysis established it as a 28-amino-acid octacosapeptide, with its complete amino acid sequence determined using enzymatic digestion techniques like kallikrein cleavage.^[8] This characterization solidified VIP's uniqueness within the glucagon/secretin superfamily.^[1]

Chemical Structure and Synthesis

Vasoactive intestinal peptide (VIP) is a 28-amino-acid linear peptide hormone with the primary sequence His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH₂.^[2] The C-terminus is amidated, a modification essential for its biological activity, while the N-terminus features a free amino group.^[9] VIP adopts an alpha-helical secondary structure, particularly in its C-terminal region spanning residues 6–26, which is crucial for high-affinity binding to its receptors.^[10] VIP belongs to the glucagon/secretin superfamily of peptides, characterized by structural homology in their N-terminal regions.^[11] It shares approximately 40% sequence identity with secretin and about 68% with pituitary adenylate cyclase-activating polypeptide (PACAP), another family member, particularly in the conserved alpha-helical domains that facilitate receptor interactions.^[12] In humans, the VIP gene (VIP) is located on chromosome 6q25.2 and encodes a prepro-VIP precursor protein of 170 amino acids.^[13] This precursor undergoes post-translational processing: signal peptidase first cleaves the N-terminal signal peptide in the endoplasmic reticulum, yielding a 149-amino-acid pro-VIP.^[1] Subsequent cleavage by prohormone convertases, such as PC1/3 and PC2, occurs in the trans-Golgi network and secretory granules, generating mature VIP along with related peptides like PHM-27 (peptide histidine-methionine).^[14] VIP is primarily synthesized in neuronal cells, including enteric neurons of the gastrointestinal tract, and in certain endocrine cells, such as those in the pancreas and adenohypophysis.^[15] Expression of the VIP gene is regulated by transcriptional factors, notably cAMP response element-binding protein (CREB), which binds to cAMP-responsive elements in the promoter region to enhance transcription.^[16] This regulation is activated in response to neural stimuli that elevate intracellular cAMP levels, such as depolarization or neurotransmitter signaling in neurons.^[17]

Receptors and Molecular Mechanisms

Receptor Types

Vasoactive intestinal peptide (VIP) primarily exerts its effects through two G protein-coupled receptors belonging to the class B family: VPAC1 (also known as VIP/PACAP receptor 1) and VPAC2 (VIP/PACAP receptor 2). A third related receptor, PAC1 (pituitary adenylate cyclase-activating polypeptide type I receptor), binds VIP with low affinity.^[18]^[19] These receptors share a common structural architecture typical of class B GPCRs, featuring seven transmembrane domains and a large extracellular N-terminal domain that is crucial for high-affinity peptide binding.^[20]^[18] The N-terminus forms initial interactions with the C-terminal region of VIP, facilitating subsequent engagement of the peptide's N-terminus with the transmembrane bundle.^[20] VPAC1 and VPAC2 exhibit high-affinity binding to VIP in the nanomolar range, with dissociation constants (Ki) typically between 0.2–16 nM, and display comparable affinities for both VIP and pituitary adenylate cyclase-activating polypeptide (PACAP).^[18]^[19] In contrast, PAC1 has low affinity for VIP (Ki ~0.5–1 μM) but high affinity for PACAP, rendering it primarily responsive to the latter peptide.^[18]^[19] VPAC2 demonstrates a slight selectivity for VIP over PACAP, with pKi values for VIP (7.8–8.8) marginally higher than for PACAP-27 (7.6–8.0).^[18] Tissue distribution of these receptors is distinct and widespread. VPAC1 is prominently expressed in the liver, lung, intestine, cerebral cortex, hippocampus, and T lymphocytes.^[18]^[19] VPAC2 shows high expression in the brain (particularly the thalamus and suprachiasmatic nucleus), heart, pancreas, and smooth muscle tissues of the cardiovascular and gastrointestinal systems.^[18]^[19] PAC1 is mainly found in the central nervous system (e.g., olfactory bulb, hypothalamus), adrenal medulla, and various neuroendocrine tissues, with limited VIP responsiveness due to its binding profile.^[18]^[19] Alternative splicing generates isoforms of these receptors, influencing their expression and potential functionality. VPAC1 and VPAC2 have limited splice variants, though five-transmembrane (5TM) isoforms of VPAC1 have been identified that may alter ligand binding or trafficking.^[21] PAC1 exhibits greater isoform diversity, including N-terminal variants such as hop and hip, which arise from alternative splicing and contribute to tissue-specific expression patterns.^[18]^[19]

Signaling Pathways

Vasoactive intestinal peptide (VIP) primarily exerts its effects through binding to its G protein-coupled receptors, VPAC1 and VPAC2, which predominantly couple to the stimulatory G protein (Gs). This coupling activates adenylyl cyclase, leading to an increase in intracellular cyclic adenosine monophosphate (cAMP) levels.^[22] The elevated cAMP then binds to and activates protein kinase A (PKA), which phosphorylates various downstream targets, including the transcription factor CREB (cAMP response element-binding protein), thereby promoting gene transcription and cellular responses such as proliferation and survival.^[23] While VPAC2 receptors are almost exclusively coupled to Gs and thus primarily signal through the cAMP-PKA pathway, VPAC1 receptors exhibit more versatility and can couple to Gq proteins in certain cell types. This Gq coupling activates phospholipase C (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 subsequently triggers the release of calcium ions (Ca²⁺) from intracellular stores, contributing to calcium-dependent signaling events like enzyme activation and cytoskeletal changes.^[12] Additionally, both receptor subtypes can engage in cross-talk with the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, often via PKA-mediated activation or β-arrestin scaffolding, influencing cell proliferation and differentiation.^[24] To regulate the duration of cAMP signaling, VIP receptor activation can indirectly modulate phosphodiesterase 4 (PDE4), the primary enzyme responsible for cAMP degradation, through PKA-dependent phosphorylation that activates it and fine-tunes its activity in specific contexts.^[25] Negative regulation of these pathways occurs via β-arrestin-mediated mechanisms following receptor phosphorylation by G protein-coupled receptor kinases (GRKs). β-Arrestins bind to the phosphorylated receptors, uncoupling them from G proteins (desensitization), promoting clathrin-dependent internalization, and facilitating receptor trafficking to endosomes for either recycling or degradation.^[26] This process prevents prolonged signaling and allows for spatiotemporal control of VIP responses.

Physiological Functions

In the Gastrointestinal System

Vasoactive intestinal peptide (VIP) plays a pivotal role in the gastrointestinal (GI) tract as a neuropeptide and hormone, primarily acting through the enteric nervous system to regulate motility, secretion, and mucosal homeostasis. Expressed abundantly in neurons of the myenteric and submucosal plexuses, VIP functions as a key mediator in non-adrenergic non-cholinergic (NANC) neurotransmission, influencing smooth muscle tone and epithelial functions to facilitate digestion and nutrient absorption.^[1] In gut motility, VIP induces relaxation of smooth muscle throughout the GI tract, primarily via activation of the VPAC2 receptor, which elevates intracellular cyclic adenosine monophosphate (cAMP) levels and inhibits contractile responses. This mechanism is essential for coordinating peristalsis and preventing excessive contractions; for instance, VIP relaxes human gastric and colonic smooth muscles, contributing to propulsive motor patterns.^[1] Additionally, VIP participates in defecation reflexes by stimulating colonic motility through interactions with corticotropin-releasing factor (CRF) pathways, where peripheral CRF activates CRF1-positive VIPergic neurons to promote expulsion and prevent stress-induced stasis.^[1]^[27] VIP stimulates water and electrolyte secretion from intestinal epithelial cells, enhancing Cl⁻ and HCO₃⁻ efflux via VPAC1 receptor-mediated cAMP signaling, which aids in digestion by maintaining luminal hydration and facilitating nutrient solubilization. In the duodenum, this promotes bicarbonate release through a CFTR-dependent pathway, supporting enzymatic activity and pH balance.^[1] Conversely, VIP inhibits gastric acid secretion by acting on VPAC1 receptors on D cells to release somatostatin, thereby protecting the gastric mucosa from acid-induced damage during digestive processes.^[1] Regarding GI homeostasis, VIP regulates gut microbiota composition and barrier integrity by promoting epithelial differentiation and reducing permeability. VIP deficiency in mice leads to dysbiosis, characterized by decreased Firmicutes/Bacteroidetes ratios and reduced short-chain fatty acid producers, increasing susceptibility to inflammation.^[28] Through VPAC1 signaling, VIP maintains microbial balance by modulating toll-like receptor pathways in enteric glia, while enhancing tight junction proteins like ZO-1 to preserve barrier function and limit bacterial translocation, as observed in models of colitis and irritable bowel syndrome.^[1]^[29] In postprandial responses, VIP contributes to coordinated secretion and motility adjustments following meals, supporting efficient nutrient processing without detailed pathway elaboration here.^[30] Recent research as of 2024 indicates that VIP promotes secretory differentiation and regeneration of intestinal epithelial progenitor cells, enhancing mucosal repair and homeostasis.^[31] Additionally, VIP supports host defense against enteropathogens by recruiting innate lymphoid cells to the gut mucosa, bolstering antimicrobial responses as of 2021.^[32]

In the Cardiovascular System

Vasoactive intestinal peptide (VIP) serves as a potent vasodilator in the cardiovascular system, exerting effects on coronary, pulmonary, and systemic arteries. Its vasodilatory action is mediated primarily through VPAC1 receptors on endothelial cells, which activate adenylyl cyclase to increase intracellular cyclic AMP (cAMP) levels, leading to the release of nitric oxide (NO) and subsequent relaxation of vascular smooth muscle.^[1]^[33] This mechanism enhances blood flow in these vascular beds, with VIP demonstrating 50- to 100-fold greater potency than acetylcholine as a vasodilator.^[33] In healthy human subjects, intravenous infusion of VIP induces sustained vasodilation, decreasing total peripheral resistance by approximately 30% and mean arterial pressure by 12%, while also reducing forearm vascular resistance by 65%.^[34] These hypotensive effects are accompanied by increased coronary blood flow, particularly during physiological stress such as ischemia, where VIP release from cardiac nerves helps regulate vasomotor tone and maintain perfusion.^[33]^[34] Beyond vascular effects, VIP directly influences cardiac function by binding to VPAC2 receptors on myocytes, producing positive inotropic and chronotropic responses that enhance contractility and heart rate.^[35] These effects occur via cAMP-mediated signaling and are more pronounced than those of norepinephrine in isolated heart preparations, contributing to autonomic regulation of cardiac output.^[33]^[35] VIP also confers cardioprotection during ischemia-reperfusion injury, improving post-ischemic left ventricular function, coronary flow, and reducing creatine kinase release and hydroxyl radical production in isolated rat hearts.^[36] This protection involves attenuation of intracellular calcium transients and oxidative stress, with evidence suggesting involvement of anti-apoptotic pathways downstream of VPAC receptor activation.^[36]^[35] In the context of pulmonary hypertension, VIP regulates vascular tone by decreasing pulmonary artery pressure and resistance through VPAC-mediated vasodilation, as demonstrated in animal models of the condition.^[37] This role highlights its potential in mitigating elevated pulmonary pressures.^[37]

In the Nervous System

Vasoactive intestinal peptide (VIP) is widely distributed as a neuropeptide throughout the central nervous system (CNS), with prominent expression in regions such as the cerebral cortex, hippocampus, and suprachiasmatic nucleus (SCN).^[38]^[39] In the cerebral cortex and hippocampus, VIP is localized primarily in interneurons, contributing to local circuit modulation.^[40] In the peripheral nervous system (PNS), VIP is expressed in enteric neurons of the myenteric and submucosal plexuses, as well as in sensory neurons within dorsal root ganglia (DRG).^[1]^[41] As a neuromodulator, VIP plays a key role in synaptic plasticity within the hippocampus, where it enhances glutamate release and facilitates long-term potentiation (LTP).^[42] In hippocampal slices, exogenous VIP application increases excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons by promoting presynaptic glutamate release, thereby strengthening glutamatergic transmission.^[43] This modulation supports LTP induction, a cellular correlate of learning and memory, through interactions with NMDA receptors and downstream signaling that amplifies synaptic efficacy.^[42] Endogenous VIP, acting via VPAC receptors, fine-tunes these processes to balance excitation in hippocampal circuits.^[42] VIP also regulates cerebral blood flow and provides neuroprotection against excitotoxicity in the CNS. Intracranial or intra-arterial administration of VIP induces dose-dependent vasodilation, increasing regional cerebral blood flow without mediation by adrenergic, cholinergic, or opioidergic pathways.^[44] This vasodilatory effect supports neuronal metabolism during heightened activity. Additionally, VIP exerts neuroprotective actions by attenuating excitotoxic damage from excessive glutamate exposure; in murine models, VIP pretreatment reduces neuronal cell death in the CNS by inhibiting caspase activation and promoting survival signaling.^[45] These properties highlight VIP's role in maintaining cerebral homeostasis under stress. In the PNS, VIP contributes to pain modulation through its expression in DRG sensory neurons, where it exhibits anti-nociceptive effects. Following peripheral nerve injury, such as sciatic axotomy, VIP levels rise markedly in small- and medium-sized DRG neurons and their central projections to the spinal cord dorsal horn, correlating with altered pain sensitivity.^[41] Intracerebroventricular VIP administration induces analgesia in rodents, suppressing nociceptive responses like the tail-flick reflex, an effect partially mediated by opioidergic mechanisms as it is reversed by naloxone.^[46] This suggests VIP dampens pain transmission via presynaptic inhibition in sensory pathways. VIP often co-localizes with related peptides in neural tissues, particularly peptide histidine methionine (PHM) in human nerves and its rodent analog peptide histidine isoleucine (PHI). Both peptides are derived from the same preproVIP precursor and are co-expressed in a subset of CNS and PNS neurons, including those in the enteric system and DRG.^[47] This co-localization enables coordinated neuromodulatory functions, such as enhanced signaling through shared receptors that elevate cyclic AMP (cAMP) levels.^[47] As of 2024, VIP has been shown to excite gonadotropin-releasing hormone (GnRH) neurons via VPAC2 receptors and KCa3.1 channels, contributing to reproductive neuroendocrine regulation.^[48]

In the Immune System

Vasoactive intestinal peptide (VIP) serves as a key immunomodulatory neuropeptide, exerting anti-inflammatory effects primarily through its interaction with VPAC2 receptors on immune cells such as T-cells and macrophages. This modulation helps maintain immune homeostasis by shifting the balance toward tolerance and away from excessive inflammation. VIP's actions in the immune system are particularly prominent in suppressing pro-inflammatory responses while promoting regulatory mechanisms, contributing to overall immune regulation.^[49] VIP inhibits the production of pro-inflammatory cytokines, including TNF-α and IL-12, in activated macrophages and T-cells via VPAC2 signaling, which reduces NF-κB activity and limits inflammatory cascades. Conversely, it promotes the expression of the anti-inflammatory cytokine IL-10 in these cells, enhancing CREB activation and fostering a suppressive microenvironment. This cytokine regulation occurs through the cAMP-PKA pathway in immune cells, as detailed in receptor signaling mechanisms. In T-cells and macrophages, these effects attenuate innate and adaptive inflammatory responses, preventing tissue damage during immune challenges.^[49]^[7] VIP suppresses Th1 and Th17 responses by downregulating key transcription factors like T-bet and RORγt, while enhancing the differentiation and expansion of regulatory T-cells (Tregs), which express FoxP3 and produce IL-10. This shift favors a Th2/Treg profile over pathogenic Th1/Th17 subsets, as observed in models of autoimmune inflammation. Additionally, VIP regulates dendritic cell (DC) maturation and migration by inducing a tolerogenic phenotype, reducing surface expression of co-stimulatory molecules like CD80 and CD86, and impairing their ability to prime pro-inflammatory T-cells. These actions on DCs promote immune tolerance and limit excessive adaptive responses.^[50]^[51]^[52] In mucosal immunity, particularly within gut-associated lymphoid tissue (GALT), VIP modulates lymphocyte proliferation, trafficking, and cytokine secretion to support barrier integrity and host defense against pathogens. It promotes the recruitment of innate lymphoid cells (ILCs) and other immune effectors to the intestinal mucosa, enhancing secretory IgA production and antimicrobial activity without triggering overt inflammation. Furthermore, VIP protects against autoimmune inflammation by strengthening epithelial barriers through upregulation of tight junction proteins like ZO-1 and occludin, thereby reducing permeability and limiting antigen access that could exacerbate autoimmunity. This barrier enhancement, combined with its immunomodulatory effects, underscores VIP's role in preventing chronic inflammatory conditions.^[53]^[54]

Specialized Roles

In Circadian Rhythms

Vasoactive intestinal peptide (VIP) is expressed in approximately 10–20% of neurons within the suprachiasmatic nucleus (SCN), the primary circadian pacemaker in mammals, particularly in the ventrolateral region where these neurons receive direct retinal input via the retinohypothalamic tract (RHT).^[55]^[56] These VIP-expressing neurons co-localize with γ-aminobutyric acid (GABA) and release VIP in a circadian manner.^[56] Within the SCN, VIP functions as a key coupling factor, synchronizing the molecular oscillations of individual clock cells to generate coherent network-level circadian rhythms essential for overall timing.^[56] VIP mediates the synchronization of SCN oscillators primarily through activation of the VPAC2 receptor, which is abundantly expressed in the nucleus and drives cell-autonomous signaling pathways, including ERK1/2 and DUSP4, to align cellular clocks.^[57] Application of VIP to SCN slices induces phase delays of up to 4 hours when administered during the early subjective night (circadian time 10), lengthening the period and reducing rhythm amplitude in a dose-dependent manner (100 nM to 10 μM).^[57] This VPAC2-dependent mechanism facilitates phase-shifting of SCN rhythms in response to light cues, with in vivo VIP injections producing acute behavioral phase shifts comparable to photic entrainment.^[57] In photic entrainment, SCN VIP neurons exhibit circadian patterns of spontaneous activity, peaking during the subjective day, and show enhanced light-evoked calcium responses around subjective dusk (circadian time 12), which are critical for normal phase resetting.^[58] Silencing these neurons reduces light-induced phase delays from approximately 2.1 hours to 0.9 hours, demonstrating their necessity for proper entrainment to the light-dark cycle.^[58] Furthermore, VIP contributes to output pathways from the SCN, promoting robust clock gene expression (e.g., Per1, Per2) in peripheral tissues such as the liver; VIP deficiency leads to dampened oscillations and altered phase relationships between central and peripheral clocks.^[59] Mice lacking VIP (VIP knockout) display profound disruptions in circadian function, including fragmented locomotor activity rhythms that initiate up to 8 hours earlier than in wild-type controls, reduced amplitude in SCN neuronal firing, and loss of behavioral rhythmicity under constant conditions.^[60] These knockouts exhibit desynchronized SCN cellular oscillators and impaired maintenance of rhythmicity, underscoring VIP's role in sustaining coherent pacemaking.^[60] Similarly, VPAC2 receptor-deficient mice show comparable fragmentation and weakened entrainment, confirming the peptide-receptor axis's indispensability.^[60] Within SCN circuitry, VIP interacts with GABA and glutamate to fine-tune circadian synchronization. These GABA-VIP interactions can be cooperative during network synchronization or antagonistic depending on the circadian phase, influencing overall excitability.^[61] Glutamate, released from RHT terminals onto VIP neurons, activates these cells during light exposure, integrating photic signals to initiate entrainment while VIP amplifies downstream synchronization.^[56] Vasoactive intestinal peptide (VIP) plays a key role in modulating social behaviors, with deficiency models revealing disruptions in affiliation and aggression. In mice, offspring of VIP-deficient mothers exhibit severe deficits in social approach behavior, particularly males, who show reduced preference for social novelty regardless of their own genotype. These impairments extend to cognitive functions supporting social interaction, such as reversal learning, and are linked to prenatal VIP signaling disruptions. Antagonist treatment during embryogenesis further impairs social recognition and interaction in adult male offspring, mimicking deficiency effects on prosocial engagement. In parallel, VIP deficiency via knockdown in avian species, such as zebra finches and waxbills, abolishes aggression while leaving other behaviors like courtship intact, indicating site-specific roles in aggressive social displays.^[62]^[63]^[64] VIP influences prosocial behaviors through interactions with the oxytocin and vasopressin systems in the hypothalamus. Intracarotid infusion of VIP in cats dose-dependently stimulates oxytocin release (peaking at 34.9 microU/ml) and vasopressin release (peaking at 157 microU/ml) from the neurohypophysis, suggesting VIP acts as a central regulator in the magnocellular hypothalamo-neurosecretory pathway to enhance affiliation and bonding. This modulation supports prosocial circuits, as hypothalamic VIP signaling promotes grouping and pair maintenance in rodents and birds. In avian models, central VPAC receptor activation via endogenous VIP drives gregariousness and affiliation, with antagonism reducing time spent with conspecifics in novel environments and altering group size preferences in zebra finches. Chronic VPAC antagonism also impairs pair bonding, decreasing pairing likelihood in later sessions.^[65]^[66]^[64] VIP further shapes social behaviors by influencing anxiety-like responses and maternal care through limbic regions. Higher plasma VIP levels correlate negatively with anxiety symptoms (r = -0.44) and positively with functional connectivity between the amygdala and prefrontal areas like the orbitofrontal cortex, as well as grey matter volume in the left amygdala and lateral orbitofrontal cortex. VIP interneurons in the medial prefrontal cortex regulate anxiety-related behaviors, with their inhibition linked to heightened emotional reactivity. In maternal contexts, anti-VIP injections in bantam hens disrupt incubation after several days, while VIP levels are elevated in incubating versus laying hens, underscoring its role in parental affiliation via hypothalamic sites. These effects highlight VIP's integration of anxiety modulation with caregiving circuits.^[67]^[68]^[69] Recent studies have strengthened links between VIP and social deficits in autism spectrum disorder (ASD) through neurodevelopmental pathways. VIP-expressing interneurons are downregulated in ASD individuals, contributing to circuit imbalances that impair social cognition.^[70] In mouse models of Dravet syndrome, a neurodevelopmental disorder with ASD features, hypoexcitability of VIP interneurons reduces sociability and spatial memory without affecting seizures, replicating core ASD social impairments via disrupted cholinergic modulation and pyramidal neuron activation. These findings position VIP signaling as a therapeutic target for ameliorating ASD-related social deficits during critical developmental windows.^[71]^[72]

Clinical Significance

Associated Pathologies

Vasoactive intestinal peptide (VIP) dysregulation manifests in various pathologies, where elevated or reduced levels contribute to disease progression. In VIPomas, rare neuroendocrine tumors primarily originating in the pancreas, excessive VIP secretion leads to the Verner-Morrison syndrome, characterized by severe secretory diarrhea, hypokalemia, metabolic acidosis, and flushing due to hypersecretion of water and electrolytes into the intestinal lumen.^[73] These tumors autonomously produce high VIP levels, disrupting gastrointestinal homeostasis and causing profound dehydration if untreated.^[74] Reduced VIP expression exacerbates inflammation in several autoimmune and chronic inflammatory conditions. In inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, colonic VIP-immunoreactive nerve fibers and peptide levels are markedly decreased compared to healthy controls, correlating with heightened mucosal inflammation and barrier dysfunction.^[75] Similarly, in asthma, airways from affected patients show absent or reduced VIP-immunoreactive nerves, impairing bronchodilation and contributing to airway hyperresponsiveness and remodeling.^[76] In rheumatoid arthritis (RA), patients exhibit low serum VIP levels and diminished VIP-mediated immune responses, promoting synovial inflammation and joint destruction through unchecked pro-inflammatory cytokine activity.^[77]^[78] VIP deficiency also plays a role in neurodegenerative disorders. In Alzheimer's disease, cerebrospinal fluid concentrations of VIP are reduced, associated with increased β-amyloid accumulation and neuronal atrophy in affected brain regions.^[79] Likewise, in Parkinson's disease, serum and neuronal VIP levels are decreased, alongside downregulation of VIP receptors, linking to dopaminergic cell loss and impaired striatal plasticity.^[80]^[81] Associations with cardiovascular and systemic inflammatory conditions further highlight VIP's pathological relevance. In pulmonary arterial hypertension (PAH), particularly idiopathic forms, VIP levels are deficient in pulmonary tissues, leading to impaired vasodilation, elevated pulmonary pressures, and vascular remodeling.^[82] During sepsis, endogenous VIP production is disrupted, contributing to vasodilation failure, endothelial dysfunction, and exacerbated systemic inflammation.^[83] VIP plays a role in metabolism and obesity regulation, with studies indicating its influence on energy homeostasis and body composition.^[84] VIP deficiency has been associated with altered gut microbiota composition in mouse models.^[85]

Therapeutic Applications

Vasoactive intestinal peptide (VIP) and its analogs have emerged as promising therapeutic agents due to their anti-inflammatory, immunomodulatory, and vasodilatory properties. In inflammatory bowel disease (IBD) and rheumatoid arthritis (RA), VIP analogs such as stearyl-norleucine-VIP (SNV) restore anti-inflammatory balance by suppressing pro-inflammatory cytokines like TNF-α and enhancing regulatory T-cell activity. Preclinical studies in murine models of dextran sulfate sodium-induced colitis and collagen-induced arthritis demonstrate that low-dose SNV administration significantly reduces disease severity, mucosal damage, and joint inflammation compared to native VIP, attributed to its enhanced stability and receptor affinity for VPAC1 and VPAC2. Similarly, sterically stabilized micelles encapsulating VIP (VIP-SSM) have shown superior efficacy in reversing severe colitis in animal models by targeted delivery to inflamed sites, minimizing systemic side effects. In respiratory disorders, inhaled formulations of VIP, particularly the synthetic analog aviptadil, induce bronchodilation and pulmonary vasodilation. Clinical trials have evaluated inhaled aviptadil for pulmonary hypertension (PH), where a single 100 μg dose during right heart catheterization improved hemodynamics, including reduced pulmonary vascular resistance and increased stroke volume, without significant adverse effects. For asthma, preclinical and early-phase studies indicate that VIP agonists like RO 25-1553 promote airway relaxation and reduce inflammation via VPAC2 signaling, positioning inhaled VIP as a potential adjunct therapy to standard bronchodilators. These applications leverage VIP's selective pulmonary effects when delivered aerosolized, enhancing efficacy while limiting gastrointestinal exposure. As of September 2025, preliminary evidence suggests inhaled aviptadil may aid recovery from post-COVID pulmonary injury.^[86] VIP exhibits neuroprotective potential in multiple sclerosis (MS) and stroke through mechanisms involving reduced neuroinflammation and promotion of remyelination. In experimental autoimmune encephalomyelitis (EAE), a model of MS, VIP administration downregulates both inflammatory and autoimmune responses, ameliorating clinical symptoms and demyelination. Preclinical stroke models further support VIP's role in mitigating ischemic injury by inhibiting microglial activation and apoptosis. Investigational applications include type 2 diabetes, where VPAC2-selective VIP agonists enhance glucose-dependent insulin secretion from pancreatic β-cells without risking hypoglycemia. Studies in rodent models and isolated islets show that potent VPAC2 agonists like RO 25-1553 improve glucose disposal and insulin release, suggesting therapeutic potential as an adjunct to existing antidiabetic agents.^[87] A major challenge in VIP therapeutics is its short plasma half-life, typically less than 1 minute, due to rapid enzymatic degradation and renal clearance. This limitation has been addressed through structural modifications such as cyclization via hydrocarbon stapling or lactam bridges, which enhance stability and VPAC2 agonism while preserving bioactivity, as demonstrated in glucose homeostasis models. PEGylation further extends half-life by conjugating polyethylene glycol chains, improving pharmacokinetics in preclinical IBD studies.

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Signal Transduction by VIP and PACAP Receptors - MDPI
VPAC1, VPAC2, and PAC1 receptors are secretin-like G protein-coupled receptors, constituting one of five main GPCR classes regulating responses to extracellular ...
[20]
Understanding VPAC receptor family peptide binding and selectivity
Nov 16, 2022 · Our work improves molecular understanding of peptide engagement with the PAC1R and VPAC1R that may benefit the development of novel selective agonists.
[21]
Identification and characterization of five-transmembrane isoforms of ...
The human vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide receptor family consists of three receptors, PAC1 (HGNC approved ...Results · Vpac1 And Vpac2 Expression... · Materials And Methods
[22]
https://doi.org/10.1074/jbc.M109.043117
[23]
IGF-I and vasoactive intestinal peptide (VIP) regulate
VIP on CREB activation was completely abolished by. Rp-cAMPS (P<0·01). These results indicate that VIP stimulates CREB phosphorylation via the cAMP/PKA pathway.
[24]
https://doi.org/10.1152/ajpcell.00001.2014
[25]
PKA-dependent activation of PDE3A and PDE4 and inhibition of ...
The results indicate that PKA regulates cAMP levels in smooth muscle via stimulatory phosphorylation of PDE3A and PDE4 and inhibitory phosphorylation of ...
[26]
https://doi.org/10.1074/jbc.M201815200
[27]
VIP is involved in peripheral CRF-induced stimulation of propulsive ...
In particular, the peptide stimulates water and electrolyte secretion from the intestine, leading to diarrhea in experimental animals and humans (6, 11, 37).
[28]
Vasoactive Intestinal Peptide Deficiency Is Associated With Altered ...
Dec 2, 2019 · Vasoactive intestinal peptide (VIP) is crucial for gastrointestinal tract (GIT) health. VIP sustains GIT homeostasis through maintenance of the ...
[29]
Vasoactive Intestinal Polypeptide Plays a Key Role in the Microbial ...
Here we show that small intestinal motility, but not gastric emptying or colonic motility, is regulated by the microbiome through modulation of vasoactive ...
[30]
Effect of vasoactive intestinal peptide on gastric secretion in the cat
Vasoactive intestinal peptide similarly enhanced the acid and pepsin responses to a liver meal in spite of a significant inhibition of the postprandial release ...
[31]
Vasoactive intestinal peptide: cardiovascular effects - PubMed
The presence and significant cardiovascular effects of VIP in the heart suggests that this peptide is important in the regulation of coronary blood flow, ...
[32]
Cardiovascular effects of vasoactive intestinal peptide in ... - PubMed
VIP infusion caused sustained vasodilatation and decreased total peripheral resistance and mean arterial pressure by 30 and 12%, respectively.
[33]
Cardioprotective role of the VIP signaling system - PubMed
Both peptides are involved in autonomic regulation of the cardiovascular system, where they exert positive inotropic and chronotropic effects, and cause ...
[34]
Protective role of intracoronary vasoactive intestinal peptide in ...
Vasoactive intestinal peptide (VIP) has been shown to exert vasodilatory action and positive ionotropic effect on the heart and to possess free ...Missing: cardiovascular | Show results with:cardiovascular
[35]
Vasoactive Intestinal Peptide as a New Drug for Treatment of ...
Vasoactive Intestinal Peptide as a New Drug for Treatment of Primary Pulmonary Hypertension. J Clin Invest. 2003 May;111(9):1339-46. doi: 10.1172/JCI17500 ...<|control11|><|separator|>
[36]
Distribution of vasoactive intestinal polypeptide in the rat ... - PubMed
Distribution of vasoactive intestinal polypeptide in the rat and mouse brain. ... Hippocampus / metabolism; Male; Mice; Nerve Fibers / metabolism; Neural Pathways ...
[37]
Distribution of vasoactive intestinal peptide and pituitary adenylate ...
Aug 30, 2004 · All three types of the VIP/PACAP receptors were expressed in the astrocytes, and the PAC1 receptors were also expressed in the oligodendrocytes.Missing: structure affinity isoforms
[38]
Distribution and morphology of vasoactive intestinal polypeptide-like ...
The distribution and morphology of vasoactive intestinal polypeptide-like (VIP-L) immunoreactive neurons were studied in thick (70-120 microns) sections ...Missing: cerebral | Show results with:cerebral
[39]
Vasoactive intestinal polypeptide (VIP) increases in the spinal cord ...
A radical change in neuropeptide metabolism of dorsal root ganglion cells occurs after peripheral axotomy, in the form of a marked increase in VIP synthesis. An ...
[40]
VIP Modulation of Hippocampal Synaptic Plasticity - PubMed Central
Jun 12, 2020 · This paper reviews the multiple roles of VIP in synaptic transmission, synaptic plasticity and hippocampal-dependent learning and memory processes.
[41]
VIP enhances both pre- and postsynaptic GABAergic transmission to ...
VIP enhances both pre- and postsynaptic GABAergic transmission to hippocampal interneurones leading to increased excitatory synaptic transmission to CA1 ...
[42]
Effect of vasoactive intestinal polypeptide on cerebral blood flow in ...
Intraarterial injection of VIP resulted in a dose-dependent increase in the cerebral blood flow. The effect was not antagonized by any of the antagonists ...
[43]
Vasoactive intestinal peptide prevents excitotoxic cell death in the ...
Vasoactive intestinal peptide (VIP) has potent growth-related actions and neuroprotective properties that influence mitosis and neuronal survival in culture.Missing: flow | Show results with:flow
[44]
Vasoactive intestinal polypeptide induces analgesia and impairs the ...
VIP decreased the analgesic effect of a single subcutaneous morphine injection and the development of chronic tolerance to morphine.
[45]
Peptide histidine-isoleucine and and its human analogue ... - PubMed
Feb 26, 2004 · PHI, PHM, PHV and VIP are co-synthesized from the same precursor and share high levels of structural and functional similarity. These peptides ...
[46]
https://pubmed.ncbi.nlm.nih.gov/9920454/
[47]
https://pubmed.ncbi.nlm.nih.gov/15069375/
[48]
https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2024.1354095/full
[49]
https://doi.org/10.3390/ijms21010065
[50]
Neuropeptide modulation of the immune response in gut ... - PubMed
These peptides may be important modulators of mucosal immunity regulating lymphocyte proliferation and trafficking in gut associated lymphoid tissue, synthesis ...
[51]
The Role of Vasoactive Intestinal Peptide and Mast Cells ... - Frontiers
Nov 24, 2021 · These findings suggested that VIP may mediate the protective effect of L.casei ATCC 393 on intestinal mucosal immune barrier dysfunction via MCs.
[52]
Vasoactive Intestinal Peptide and the Mammalian Circadian System
Vasoactive intestinal peptide (VIP), defines a cell population within the SCN and is likely used as a signaling molecule by these neurons.
[53]
Vasoactive intestinal peptide controls the suprachiasmatic circadian ...
Feb 1, 2019 · We show that SCN slices in organotypic culture demonstrate rapid and sustained circuit-level circadian responses to VIP that are mediated at a cell-autonomous ...
[54]
SCN VIP Neurons Are Essential for Normal Light-Mediated ...
We conclude that SCN VIP neurons exhibit circadian rhythms in spontaneous and light-responsive activity and are essential for the normal resetting of daily ...
[55]
Effects of Vasoactive Intestinal Peptide Genotype on Circadian Gene ...
The VIP-deficient mice exhibited low amplitude rhythms in the SCN as well as altered phase relationships between the SCN and the peripheral oscillators.
[56]
Disrupted circadian rhythms in VIP- and PHI-deficient mice - PubMed
The VIP/PHI-deficient mice exhibited pronounced abnormalities in their circadian system. The activity patterns started approximately 8 h earlier than predicted ...
[57]
The Suprachiasmatic Nucleus (SCN) from Genes to Neurons to ...
Nov 12, 2014 · Interestingly, GABA signaling interacts with VIP signaling in either a cooperative or antagonistic manner depending on the state of the network.
[58]
Deficits in social behavior and reversal learning are more prevalent ...
All male offspring of VIP deficient mothers exhibited severe deficits in social approach behavior and reversal learning.Missing: aggression | Show results with:aggression
[59]
Vasoactive intestinal peptide antagonist treatment during mouse ...
VIP antagonist treatment during embryogenesis also had permanent effects on adult brain chemistry and impaired social recognition behavior in adult male mice.
[60]
New perspectives on vasoactive intestinal polypeptide as a ...
The present review highlights new roles for VIP signaling in avian social behaviors such as affiliation, gregariousness, pair bonding and aggression.
[61]
Vasoactive Intestinal Peptide (VIP) Stimulates Oxytocin ... - PubMed
These data suggest that endogenous VIP may play a role as a neurotransmitter in the magnocellular hypothalmo-neurosecretory system.Missing: prosocial | Show results with:prosocial
[62]
https://pmc.ncbi.nlm.nih.gov/articles/PMC2422862/
[63]
Vasoactive intestinal polypeptide plasma levels associated ... - Nature
Jan 14, 2021 · Vasoactive intestinal polypeptide (VIP), first isolated and identified from porcine intestines, is a neuropeptide hormone found throughout the ...
[64]
Stress-type specific changes of VIP signaling in limbic regions of the ...
Oct 31, 2025 · For example, VIP interneurons in the medial prefrontal cortex have been shown to regulate anxiety-related behavior, with their inhibition ...Missing: maternal | Show results with:maternal
[65]
The Role of VIP in Social Behavior: Neural Hotspots ... - ResearchGate
Aug 6, 2025 · Notably, some gut peptides are involved in social functions. Examples include secretin, whose gene knockout in mice leads to social interaction ...<|separator|>
[66]
https://doi.org/10.1210/endo-115-4-1648
[67]
Unspooling the Thread: VIP Interneurons Linked With Autism Spectrum Disorder Behaviors but Not Seizures in Dravet Syndrome - Raquel Miralles, Manoj K. Patel, 2024
### Key Findings Linking VIP Interneurons to ASD Behaviors
[68]
VIPoma - StatPearls - NCBI Bookshelf - NIH
VIPomas are rare neuroendocrine tumors of the pancreas that secrete vasoactive intestinal peptide (VIP), leading to profound watery diarrhea, hypokalemia, and ...Continuing Education Activity · Introduction · Pathophysiology · Evaluation
[69]
VIPomas: Practice Essentials, Background, Pathophysiology and ...
Nov 1, 2024 · VIPomas are neuroendocrine tumors that secrete vasoactive intestinal peptide (VIP) autonomously. They originate in amine precursor uptake ...
[70]
Colonic vasoactive intestinal peptide nerves in inflammatory bowel ...
The results showed that, as compared with controls, there is a marked decrease of vasoactive intestinal peptide-immunoreactive nerve fibers in the lamina ...
[71]
Vasoactive Intestinal Polypeptide and Asthma
May 11, 1989 · They found that sections of airways from each of five subjects with asthma failed to show any nerves immunoreactive to VIP, in contrast to the ...
[72]
Vasoactive intestinal peptide gene polymorphisms, associated with ...
Feb 1, 2018 · We previously reported that early arthritis (EA) patients with low vasoactive intestinal peptide (VIP) serum levels demonstrate a worse ...
[73]
Genetic association of vasoactive intestinal peptide receptor with ...
Mar 27, 2008 · Vasoactive intestinal peptide (VIP) has been shown to be one of the endogenous factors involved in the maintenance of immune tolerance.
[74]
Low cerebrospinal fluid concentrations of peptide histidine valine ...
... Alzheimer's disease: Altered processing of prepro-vasoactive intestinal peptide and prepro-somatostatin ... reduced in Alzheimer's disease and Down's syndrome.Missing: decreased | Show results with:decreased
[75]
Correlation of Decreased Serum Pituitary Adenylate Cyclase ...
Sep 7, 2021 · The aim of the current study was to evaluate serum PACAP and VIP levels in PD patients and to analysis the correlation between neuropeptide levels and non- ...
[76]
Downregulation of neuronal vasoactive intestinal polypeptide in ...
Colonic motor and rectal sensory functions are impaired in most parkinsonian constipated patients. Compared to controls, they display a decreased number of ...
[77]
Inhalation of vasoactive intestinal peptide in pulmonary hypertension
In idiopathic pulmonary arterial hypertension (PAH) the vasodilating vasoactive intestinal peptide (aviptadil) is deficient.
[78]
The role of endothelium and endogenous vasoactive substances in ...
The role of various vasoactive substances, whose production, secretion and action are seriously impaired during sepsis is very important in vascular tone ...
[79]
Vasoactive Intestinal Peptide (VIP) in COVID-19 Therapy ... - NIH
Mar 16, 2025 · Vasoactive intestinal peptide (VIP) is known for its immune-modulating effects by suppressing the release of pro-inflammatory cytokines and enhancing ...
[80]
Vasoactive Intestinal Peptide Deficiency Is Associated With Altered ...
In some studies, VIP knockout mice were more susceptible to chemically-induced intestinal inflammation, and human inflammatory bowel disease (IBD) patients show ...
[81]
PACAP and VIP Neuropeptides' and Receptors' Effects on Appetite ...
The PACAP and VIP pathways have been linked to the regulation of body weight and fat mass accumulation, and to the development of obesity and metabolic syndrome ...<|control11|><|separator|>