--- title: "VIP (Vasoactive Intestinal Peptide)" slug: "vip" type: "compound" category: "Cognitive" url: "https://peptidesciencethailand.com/compounds/vip" description: "A 28-amino-acid neuropeptide with wide-ranging roles in immune regulation, vasodilation, and neuroprotection. Research summary and therapeutic interest areas." --- # VIP (Vasoactive Intestinal Peptide) *Neuroprotective Vasoactive Peptide, Modulating Neuroimmune and Vascular Function* **Category:** Cognitive **Format:** Lyophilized Vial **Amount:** 5mg **Purity:** >98% (HPLC) ## Overview Vasoactive Intestinal Peptide (VIP) is a 28-amino acid linear neuropeptide belonging to the glucagon/secretin superfamily of regulatory peptides. First isolated from porcine small intestine by Said and Mutt in 1970, VIP was initially characterized for its potent vasodilatory properties. Subsequent decades of research revealed that VIP functions as a widely distributed neuropeptide and neuromodulator, expressed throughout the central and peripheral nervous systems, immune system, gastrointestinal tract, pulmonary epithelium, and cardiovascular tissues. Its amino acid 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) is highly conserved across mammalian species, reflecting its fundamental biological importance. VIP exerts its biological effects through two high-affinity G-protein coupled receptors: VPAC1 (also known as VIPR1) and VPAC2 (VIPR2). Both receptors couple primarily to the stimulatory Gs protein, activating adenylyl cyclase to increase intracellular cyclic AMP (cAMP) concentrations. VPAC1 receptors are widely distributed in the cerebral cortex, hippocampus, lung, liver, and T lymphocytes, while VPAC2 receptors predominate in the thalamus, suprachiasmatic nucleus, smooth muscle, and pancreatic beta cells. This differential receptor distribution enables VIP to exert tissue-specific effects throughout the body. In the central nervous system, VIP functions as both a neurotransmitter and neuromodulator, playing critical roles in circadian rhythm regulation, neuroprotection, neurogenesis, and synaptic plasticity. VIP-expressing neurons in the suprachiasmatic nucleus (SCN) of the hypothalamus are essential for maintaining circadian clock synchronization, coordinating rhythmic gene expression across peripheral tissues. Research published in the Journal of Neuroscience has demonstrated that VIP knockout mice exhibit severely disrupted circadian rhythms, demonstrating the peptide's indispensable role in biological timekeeping. The neuroprotective properties of VIP have been extensively documented in preclinical models of neurodegeneration, stroke, and traumatic brain injury. VIP activates the cAMP/PKA/CREB signaling axis in neurons, upregulating expression of brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeleton-associated protein (Arc), and anti-apoptotic Bcl-2 family members. In models of glutamate excitotoxicity and oxidative stress, VIP administration significantly reduces neuronal cell death through these neurotrophic and anti-apoptotic mechanisms. Studies in the Annals of Neurology and related journals have demonstrated VIP's ability to reduce infarct volume in animal models of ischemic stroke when administered within a therapeutic window following the ischemic event. VIP's immunomodulatory functions represent another critical dimension of its biological activity. The peptide acts as an endogenous anti-inflammatory mediator, suppressing the production of pro-inflammatory cytokines (TNF-alpha, IL-6, IL-12) by activated macrophages and dendritic cells while simultaneously promoting the generation of regulatory T cells (Tregs) and anti-inflammatory cytokines (IL-10, TGF-beta). These effects are mediated primarily through VPAC1 receptor activation on immune cells, which inhibits NF-kappaB nuclear translocation and MAPK signaling pathways that drive inflammatory gene transcription. In the pulmonary system, VIP has attracted considerable research interest for its roles in bronchodilation, pulmonary vascular regulation, and surfactant production. VIP receptors are densely expressed in pulmonary smooth muscle, airway epithelium, and pulmonary vascular endothelium. Research has explored VIP's potential relevance in models of pulmonary arterial hypertension, where reduced VIP expression correlates with vascular remodeling and elevated pulmonary artery pressure. Studies published in the journal Circulation and other cardiovascular research journals have investigated the effects of VIP supplementation on pulmonary hemodynamics in animal models and small clinical studies. The gastrointestinal effects of VIP include stimulation of water and electrolyte secretion, relaxation of gastrointestinal smooth muscle, and modulation of gut mucosal blood flow. VIP is a principal neurotransmitter in the enteric nervous system, where it coordinates digestive motility patterns and secretory function. Dysregulation of VIP signaling has been implicated in functional gastrointestinal disorders, and research continues to explore the peptide's role in maintaining gut barrier integrity and mucosal immune homeostasis. Pharmacologically, native VIP has a very short plasma half-life of approximately 1 to 2 minutes due to rapid enzymatic degradation by dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidase. This rapid clearance has driven research into stabilized VIP analogs and alternative delivery strategies to extend its biological activity in vivo. Current research approaches include PEGylation, lipid nanoparticle encapsulation, and the development of metabolically resistant VIP analogs that maintain receptor binding affinity while resisting enzymatic degradation. The breadth of VIP's biological activities across neural, immune, vascular, and endocrine systems positions it as a uniquely multifunctional neuropeptide with research relevance spanning neuroscience, immunology, pulmonology, and gastroenterology. Ongoing investigations continue to elucidate the therapeutic potential of VIP-based interventions across these diverse clinical domains. ## Mechanism of Action ### Step 1: VPAC1/VPAC2 Receptor Engagement VIP binds with high affinity to VPAC1 and VPAC2 G-protein coupled receptors distributed across neural, immune, vascular, and epithelial tissues. Receptor subtype distribution determines tissue-specific downstream effects. ### Step 2: Adenylyl Cyclase Activation & cAMP Production Receptor engagement activates Gs-coupled adenylyl cyclase, elevating intracellular cyclic AMP concentrations. cAMP activates protein kinase A (PKA), initiating phosphorylation cascades that modulate gene expression through CREB transcription factor activation. ### Step 3: Neuroprotective Gene Transcription PKA-mediated CREB phosphorylation in neurons drives transcription of neuroprotective genes including BDNF, Bcl-2 anti-apoptotic factors, and activity-regulated cytoskeleton-associated protein (Arc), collectively enhancing neuronal survival under stress conditions. ### Step 4: NF-kappaB Inhibition & Immune Modulation VPAC1 activation on macrophages and dendritic cells inhibits NF-kappaB nuclear translocation and MAPK signaling, suppressing pro-inflammatory cytokine production (TNF-alpha, IL-6, IL-12) while promoting regulatory T cell differentiation and IL-10 release. ### Step 5: Vascular Smooth Muscle Relaxation cAMP elevation in vascular smooth muscle cells activates PKA-dependent phosphorylation of myosin light chain kinase, reducing intracellular calcium sensitivity and promoting vasodilation. This mechanism underlies VIP's effects on systemic and pulmonary vascular tone. ## Researched Benefits ### Neuroprotection and Neurotrophic Support VIP activates the cAMP/PKA/CREB pathway in neurons, upregulating BDNF and anti-apoptotic gene expression. Preclinical research demonstrates significant neuroprotective effects in models of ischemic stroke, excitotoxicity, and neurodegeneration, with reduced neuronal cell death and preserved synaptic function. ### Anti-Inflammatory Immune Modulation Through VPAC1 receptor activation on immune cells, VIP suppresses NF-kappaB-driven inflammatory cytokine production while promoting regulatory T cell differentiation. This endogenous anti-inflammatory mechanism offers a distinct profile from conventional immunosuppressive approaches by selectively modulating inflammatory balance. ### Circadian Rhythm Regulation VIP-expressing neurons in the suprachiasmatic nucleus are essential for circadian clock synchronization across peripheral tissues. Research demonstrates that VIP signaling coordinates rhythmic gene expression patterns critical for sleep-wake cycling, hormonal rhythms, and metabolic timing. ### Pulmonary and Vascular Function VIP mediates vasodilation in both systemic and pulmonary vasculature through cAMP-dependent smooth muscle relaxation. Research has explored VIP's relevance in models of pulmonary arterial hypertension and bronchodilation, with studies documenting its effects on pulmonary hemodynamics and airway smooth muscle tone. ## Dosage & Administration | Parameter | Detail | | --- | --- | | Protocol | 50-200mcg per day, dosing varies significantly based on the specific research application and route of administration | | Route | Subcutaneous injection | | Duration | Variable, typically 4-12 weeks depending on the research protocol | | Cycle Notes | VIP has a very short plasma half-life (approximately 1-2 minutes), which influences dosing frequency considerations. Some research protocols utilize multiple daily administrations or sustained-release formulations to maintain effective peptide concentrations. | | Reconstitution | Reconstitute with bacteriostatic water. Using a 5mg vial with 2mL bacteriostatic water yields 2500mcg/mL concentration. Store reconstituted solution refrigerated at 2-8C and use within 21 days. VIP is sensitive to degradation and should be handled with care. | > **Specialist note:** A your specialist will evaluate cardiovascular status, blood pressure parameters, pulmonary function, and immune system status before designing a VIP protocol. Due to VIP's potent vasodilatory effects, individuals taking antihypertensive medications or those with hypotensive conditions require careful assessment and monitoring. ## Compound Reference Data | Property | Value | | --- | --- | | Format | Lyophilized Powder | | Amount | 5mg per vial | | Purity | >98% | | Purity Method | HPLC (High-Performance Liquid Chromatography) | | 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 | | Molecular Weight | 3326.82 g/mol | | Storage | Store lyophilized powder at -20C. Reconstituted solution at 2-8C. Protect from light and moisture. | | Appearance | White to off-white lyophilized powder | ## Medical Guidance VIP is a potent vasodilator and neuromodulator with effects spanning the cardiovascular, immune, pulmonary, and nervous systems. Its broad receptor distribution means that VIP administration can influence blood pressure, heart rate, immune function, and gastrointestinal motility simultaneously. A thorough cardiovascular and immunological assessment is essential before initiating any VIP protocol, particularly for individuals with existing hypotension, autoimmune conditions, or those taking cardiovascular medications. ## Frequently Asked Questions ### What is VIP and where is it naturally produced in the body? Vasoactive Intestinal Peptide (VIP) is a 28-amino acid neuropeptide belonging to the glucagon/secretin superfamily. Despite its name suggesting gastrointestinal origin, VIP is widely distributed throughout the body. It is produced by neurons in the central and peripheral nervous systems, immune cells, pulmonary epithelium, and the enteric nervous system of the gastrointestinal tract. It functions as both a neurotransmitter and a hormonal signaling molecule. ### What receptors does VIP act through? VIP acts through two G-protein coupled receptors: VPAC1 (VIPR1) and VPAC2 (VIPR2). Both receptors activate adenylyl cyclase to increase cAMP, but they have distinct tissue distributions. VPAC1 predominates in the cerebral cortex, lung, liver, and T lymphocytes, while VPAC2 is concentrated in the thalamus, suprachiasmatic nucleus, smooth muscle, and pancreatic beta cells. This differential distribution enables tissue-specific effects. ### Why does VIP have such a short half-life? VIP's plasma half-life of approximately 1-2 minutes results from rapid enzymatic degradation by dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidase, both of which are abundant in plasma and on endothelial cell surfaces. This rapid clearance is a natural regulatory mechanism, as VIP is designed to act locally at nerve terminals and in tissue microenvironments rather than as a circulating hormone. Research into stabilized VIP analogs aims to extend its biological activity. ### Is specialist supervision required for VIP protocols? Yes. VIP's potent vasodilatory effects can significantly lower blood pressure, and its immunomodulatory actions influence inflammatory and immune regulatory pathways. A specialist must assess cardiovascular status, blood pressure baseline, pulmonary function, immune system health, and current medications before designing a VIP protocol. Monitoring during administration is essential to manage hemodynamic effects and ensure appropriate dosing. ### How should VIP be stored and reconstituted? Store lyophilized VIP at -20C protected from light and moisture. VIP is more sensitive to degradation than many other peptides, so careful handling is important. Reconstitute by slowly adding bacteriostatic water along the vial wall. A 5mg vial reconstituted with 2mL yields 2500mcg/mL. Store the reconstituted solution at 2-8C and use within 21 days. Avoid repeated freeze-thaw cycles and temperature fluctuations. ## Related Compounds - /compounds/semax - /compounds/selank - /compounds/dsip