VIP (Vasoactive Intestinal)

What is VIP (Vasoactive Intestinal Peptide)?

Vasoactive Intestinal Peptide (VIP) is a synthetic 28-amino acid neuropeptide belonging to the glucagon/secretin peptide hormone superfamily, whose members include secretin, pituitary adenylate cyclase-activating polypeptide (PACAP), glucagon, glucagon-like peptides (GLP-1/GLP-2), gastric inhibitory peptide (GIP), and growth hormone-releasing hormone (GHRH). VIP was first isolated from porcine small intestinal tissue by Sami I. Said and Viktor Mutt in 1970, where it was characterised as a vasodilator peptide. The compound was subsequently shown to have a vastly broader distribution and functional repertoire than its original classification suggested, emerging over the following five decades as one of the most pharmacologically versatile neuropeptides in mammalian biology.

VIP is distributed throughout the central nervous system, peripheral nervous system, and numerous non-neural tissues, including the immune system, cardiovascular system, respiratory epithelium, gastrointestinal tract, and endocrine pancreas. Its biological effects are mediated through two class II Gαs-coupled seven-transmembrane G protein-coupled receptors — VPAC1 (widely expressed in brain, liver, lung, small intestine, and T lymphocytes) and VPAC2 (predominantly expressed in smooth muscle, brain, and pancreatic islets) — both of which transduce VIP signalling primarily through adenylyl cyclase activation and cAMP/PKA-dependent downstream pathways. VIP also binds the PAC1 receptor with lower affinity than its primary ligand PACAP.

In healthy human subjects, serum VIP concentrations are approximately 40 pg/mL. Aviptadil is the International Nonproprietary Name (INN) for synthetic VIP used in pharmaceutical and clinical research contexts. Research-grade VIP from RCDbio is not a pharmaceutical product and is not approved for any use outside laboratory research contexts. It is not approved by the Food and Drug Administration for human or veterinary use. It is not a dietary supplement and is not intended for human consumption or therapeutic self-administration. All RCDbio research compounds are supplied strictly for laboratory and research purposes only.

Chemical Properties

How Does VIP Work?

VIP's pharmacological activity is mediated through VPAC1 and VPAC2 receptor agonism across an exceptionally broad range of tissue and cell types, initiating cAMP/PKA-dependent signalling cascades with context-specific downstream effects.

VPAC1 and VPAC2 Receptor Activation — cAMP/PKA Pathway

Both VPAC1 and VPAC2 are Class II (secretin family) GPCRs coupled to Gαs proteins. VIP binding induces receptor conformational change, Gαs activation, and adenylyl cyclase stimulation, generating elevated intracellular cAMP concentrations and downstream protein kinase A (PKA) activation. At VPAC1 — expressed predominantly in brain, liver, lung, small intestine, and T lymphocytes — VIP exerts neuromodulatory, immunomodulatory, and bronchodilatory effects through cAMP-dependent transcriptional programmes. At VPAC2 — expressed in smooth muscle, brain, and pancreatic islets — VIP modulates smooth muscle relaxation, circadian rhythm regulation at the suprachiasmatic nucleus (SCN), and glucose-dependent insulin secretion in pancreatic beta cells [Laburthe et al., 2000; Dubois-Dauphin et al., 2012].

An alanine-scanning mutagenesis study of all 28 VIP positions identified that substitution of His1, Val5, Arg14, Lys15, Lys21, Leu23, and Ile26 produced the greatest reduction in VPAC1 binding affinity and cAMP stimulation — defining the functional pharmacophore of the VIP sequence at its primary receptor [Laburthe et al., 2000]. The central alpha-helical region (Val5 to Asn24) is the primary receptor-binding domain; the N-terminus (His1) provides the activation signal following C-terminal receptor recognition.

Immunomodulatory Pathway — Anti-Inflammatory and Regulatory T Cell Effects

VIP is one of the most extensively investigated neuropeptide immunomodulators. In immune cell preparations, VIP VPAC1-mediated cAMP/PKA signalling suppresses LPS-induced proinflammatory cytokine production in macrophages (including TNF-α, IL-6, IL-12, and nitric oxide), inhibits Th1 T cell proliferation and IL-2 production, and promotes Th2 cytokine expression. VIP induces regulatory T cell (Treg) differentiation and inhibits dendritic cell maturation, establishing an anti-inflammatory and tolerogenic immune environment in isolated cell preparations and rodent inflammatory model systems [Delgado et al., 2004]. These immunomodulatory properties have generated research interest in VIP as a preclinical tool compound in rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and sepsis models.

Smooth Muscle Relaxation and Vascular Effects

VIP acts as a potent smooth muscle relaxant through VPAC receptor-mediated cAMP-dependent inhibition of myosin light chain kinase activity and potassium channel activation. In vascular smooth muscle, VIP induces vasodilation; in airway smooth muscle, bronchodilation; in intestinal smooth muscle, inhibition of peristaltic contractions. These vasodilatory and bronchodilatory effects were the original characterisation features of VIP upon its isolation in 1970 and remain central to its investigation in pulmonary hypertension and airway disease preclinical models.

Pancreatic Islet and Glucose Homeostasis Pathway

In pancreatic beta cells, VPAC2 agonism activates cAMP/PKA and Epac pathways — closing ATP-sensitive K+ channels, causing membrane depolarisation, and triggering calcium influx through voltage-gated calcium channels to stimulate glucose-dependent insulin secretion [Li et al., 2022]. VIP also promotes islet beta cell proliferation through forkhead box M1 (FOXM1) pathway activation in preclinical preparations. This glucose-dependent insulin secretion mechanism has generated research interest in VPAC2-selective agonists as incretin-related therapeutic targets.

Neuropeptide and Neurotransmitter Functions

In the central nervous system, VIP is distributed in cortical neurons, the suprachiasmatic nucleus, hippocampus, and the peripheral autonomic nervous system. VIP-expressing neurons in the SCN regulate circadian rhythm maintenance and are key pacemaker neurons. VIP modulates cholinergic and serotonergic neurotransmission in cortical preparations and acts as a neuroprotective factor in neuronal cell culture systems.

Key Research Findings

In preclinical and in vitro research contexts, VIP has been associated with the following observations:

• VPAC1/VPAC2 receptor pharmacophore mapping: Alanine-scanning mutagenesis identified His1, Val5, Arg14, Lys15, Lys21, Leu23, and Ile26 as critical residues for VPAC1 binding and cAMP stimulation; N-terminal His1 required for receptor activation; C-terminal domain required for receptor recognition [Laburthe et al., 2000].
• Immunomodulation in preclinical models: VIP suppresses LPS-induced TNF-α, IL-6, and IL-12 in macrophage preparations; inhibits Th1 proliferation; induces Treg differentiation; reduces inflammatory lesion severity in rodent models of rheumatoid arthritis, colitis, and uveitis [Delgado et al., 2004].
• Glucose-dependent insulin secretion: VPAC2 activation in pancreatic islet preparations produces cAMP/PKA-dependent glucose-dependent insulin secretion; VPAC2-selective agonists investigated as novel incretin axis research tools [Li et al., 2022].
• Circadian rhythm regulation: VIP-expressing neurons in the SCN are identified as essential pacemaker neurons; VIP-null mice show severely disrupted circadian locomotor rhythm and impaired synchronisation with light-dark schedule in rodent model studies.
• Neuroprotective activity: VIP promoted neuronal survival and reduced apoptosis in isolated cortical and hippocampal neuron preparations under oxidative stress and excitotoxic conditions in cell culture systems.

All findings listed above are derived from preclinical in vitro and in vivo data and limited clinical observations. These observations do not constitute evidence of efficacy or safety for research-grade VIP in any human condition or organism.

What are the Potential Research Applications of VIP?

In controlled laboratory environments, VIP has been investigated for the following research applications. These do not constitute claims of efficacy or safety in any organism.

VPAC1/VPAC2 Receptor Pharmacology and Structure-Activity Studies. VIP is employed as the primary endogenous reference agonist for Class II GPCR VPAC1/VPAC2 receptor pharmacology. Research employs radioligand binding displacement, cAMP accumulation assays, BRET/FRET signalling studies, and β-arrestin recruitment assays to define VIP's pharmacological profile at each receptor and as the reference against which VPAC1-selective, VPAC2-selective, and dual agonists are characterised.

Immunomodulation and Inflammatory Pathway Research. In macrophage, dendritic cell, T cell, and regulatory T cell preparations, VIP is employed as the primary immunomodulatory neuropeptide reference compound. Research characterises cAMP-dependent anti-inflammatory gene expression programmes, Treg induction mechanisms, and therapeutic potential in preclinical models of rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and sepsis.

Pancreatic Islet Biology and Incretin Axis Research. In isolated islet and beta cell preparations, VIP is employed to characterise VPAC2-mediated glucose-dependent insulin secretion, beta cell proliferation via FOXM1 pathway, and cAMP/Epac signalling dynamics — research relevant to incretin axis biology and VPAC2-selective agonist drug discovery.

Circadian Biology and SCN Neuropeptide Research VIP is employed in suprachiasmatic nucleus electrophysiology, VIP-VPAC2 signalling studies, and VIP-null mouse model preparations to characterise the role of this neuropeptide in circadian pacemaker function and light-dark cycle synchronisation.

Pulmonary Biology and Airway Smooth Muscle Research. In airway smooth muscle cell preparations and rodent pulmonary hypertension models, VIP is investigated for VPAC-mediated bronchodilatory activity, endothelial NO production, and vasodilatory pathway modulation.

What are the Potential Side Effects of VIP?

The following observations are from preclinical and limited clinical pharmacology data.

• Hypotensive effect — VIP produces dose-dependent vasodilation and systemic blood pressure reduction in rodent and human pharmacology preparations; at research-relevant doses in preclinical in vivo models, cardiovascular monitoring is relevant
• Tachycardia and cardiac output increase — vasodilatory response in preclinical preparations includes reflex tachycardia and increased cardiac output; observed in rodent and human IV administration studies
• Plasma half-life of approximately 1–2 minutes in circulation due to rapid peptidase cleavage; acute effects are therefore transient in vivo
• Diarrhoea-like effects at high doses in rodent in vivo preparations — consistent with VIP's intestinal smooth muscle relaxant and electrolyte secretion stimulating activity at enterocyte VPAC1 receptors
• No human safety or tolerability data have been established for research-grade VIP. These observations are from pharmacological studies and should not be extrapolated to research-grade material.

Risk & Handling

Handling Precautions

VIP should only be handled by trained laboratory personnel. Appropriate PPE is required: nitrile gloves, a laboratory coat, and eye protection at a minimum. When working with lyophilized powder, use within a laminar flow cabinet. Avoid aerosol generation during reconstitution. For initial dissolution, 1% acetic acid in sterile water is recommended before dilution into an aqueous buffer. The methionine residue at position 17 is susceptible to oxidative modification under aerobic conditions — minimise oxygen exposure during handling.

Exposure Risks

Risk Tier: MODERATE

VIP is a potent, broad-spectrum neuropeptide agonist at VPAC1 and VPAC2 receptors expressed across cardiovascular, immune, pulmonary, gastrointestinal, and neuroendocrine tissues. Accidental systemic exposure may produce vasodilation, hypotension, smooth muscle relaxation, and immunomodulatory effects. The extremely short plasma half-life (~1–2 minutes) limits the duration of effects from accidental systemic exposure. No human safety data has been established for research-grade VIP.

Storage

• Lyophilized form: Store at −20°C in original sealed, light-protected container with desiccant
• Reconstituted form: Store at 4°C in 1% acetic acid solution; use within 48–72 hours
• Do not subject to repeated freeze-thaw cycles; Met17 residue is particularly susceptible to oxidative modification
• Protect from light; avoid alkaline pH conditions which may promote peptide degradation.

Frequently Asked Questions

Q: What is VIP, and what is it investigated for in research? A: VIP (Vasoactive Intestinal Peptide; 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 a synthetic 28-amino acid glucagon/secretin superfamily neuropeptide first isolated by Said and Mutt in 1970. It is investigated in preclinical research contexts for VPAC1/VPAC2 receptor pharmacology, immunomodulatory pathway research, smooth muscle biology, pancreatic islet incretin signalling, circadian rhythm biology, and neuroprotection studies. It is not approved by the FDA and is intended strictly for laboratory research purposes.

Q: What is the difference between VPAC1 and VPAC2, and how does VIP interact with each? A: VPAC1 is expressed widely, including in the brain, liver, lung, small intestine, and T lymphocytes — it is the primary immune system VIP receptor. VPAC2 is expressed predominantly in smooth muscle, certain brain regions, including the SCN, and pancreatic islets — it is the primary circadian rhythm and glucose-dependent insulin secretion receptor. Both are Gαs-coupled Class II GPCRs that signal through cAMP/PKA. VIP binds both with high but not equivalent affinity; an alanine-scanning study identified the specific residues most critical for VPAC1 activity and provided the basis for VPAC1-selective and VPAC2-selective analogue design [Laburthe et al., 2000].

Q: What is Aviptadil? A: Aviptadil is the International Nonproprietary Name (INN) for synthetic VIP. It is the pharmaceutical designation used in clinical research protocols examining VIP as a therapeutic agent for pulmonary conditions, including pulmonary arterial hypertension and COVID-19-associated respiratory failure (investigated in clinical trials). Research-grade VIP from RCDbio is not a pharmaceutical product and is not approved or intended for human use.

Q: Why is VIP important in immunology research? A: VIP is one of the most extensively characterised neuropeptide immunomodulators in the field. Through VPAC1 on T cells, macrophages, and dendritic cells, VIP suppresses proinflammatory cytokine production (TNF-α, IL-6, IL-12), inhibits Th1 responses, promotes regulatory T cell differentiation, and inhibits dendritic cell maturation — establishing an anti-inflammatory and tolerogenic immune environment in preclinical cell and model systems. These activities have generated extensive research interest across autoimmune and inflammatory disease model systems [Delgado et al., 2004].

Q: What is the plasma half-life of VIP? A: VIP has an extremely short plasma half-life of approximately 1–2 minutes in circulation due to rapid cleavage by neutral endopeptidase (neprilysin), dipeptidyl peptidase IV, and other circulating and tissue peptidases. This rapid degradation limits its utility as a systemically administered research tool in preclinical in vivo models, driving the development of protease-resistant VIP analogues for extended-action research protocols.

Q: How should VIP be dissolved and stored? A: Lyophilized VIP should be stored at −20°C in a sealed, light-protected container. For initial dissolution, 1% acetic acid in sterile water is recommended before dilution into physiological buffer — direct dissolution in neutral aqueous buffer may result in poor solubility due to the peptide's amphiphilic character. Reconstituted VIP in acetic acid solution should be stored at 4°C and used within 48–72 hours. Protect from light and avoid atmospheric oxygen exposure to preserve Met17 integrity. Visit RCD Bio to explore our full research compound catalog.