Vasoactive Intestinal Peptide
Also Known AsVIP · Vasoactive Intestinal Polypeptide · PHM-27 · Aviptadil (pharmaceutical name)
VIP was discovered in 1970 by Sami Said and Viktor Mutt during purification of porcine lung extracts seeking vasodilatory substances. It was identified as a 28-amino-acid neuropeptide belonging to the secretin/glucagon superfamily. VIP is widely distributed throughout the central and peripheral nervous systems, gastrointestinal tract, and immune system, functioning as both a neurotransmitter and paracrine immunomodulator.
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-NH₂How VIP Works
VPAC1/VPAC2 Receptor Signaling
VIP binds VPAC1 and VPAC2 G-protein-coupled receptors with equal affinity. Both couple to Gs, activating adenylyl cyclase and increasing intracellular cAMP. VPAC1 predominates in the lung, liver, and T lymphocytes. VPAC2 predominates in the CNS, smooth muscle, and pancreatic beta cells. cAMP-PKA signaling mediates the majority of VIP's downstream effects.
Anti-inflammatory & Immunomodulatory Signaling
VIP suppresses Th1/Th17 inflammatory responses while promoting Th2/Treg differentiation. It inhibits NF-κB activation in macrophages, reducing TNF-α, IL-6, and IL-12 production. VIP induces tolerogenic dendritic cells and promotes regulatory T cell expansion — mechanisms that underlie its potent anti-inflammatory effects without broad immunosuppression.
Pulmonary Vasodilation & Surfactant Regulation
VIP is the primary non-adrenergic non-cholinergic (NANC) bronchodilator and pulmonary vasodilator. It relaxes airway and pulmonary vascular smooth muscle via cAMP/PKA-mediated inhibition of myosin light chain kinase. VIP also stimulates surfactant production by type II alveolar epithelial cells, critical for alveolar stability.
Neuroprotection & Circadian Regulation
VIP-expressing neurons in the suprachiasmatic nucleus (SCN) are essential for circadian rhythm synchronization. VIP drives intercellular coupling of SCN clock neurons via VPAC2. In neuroprotection models, VIP promotes neuronal survival via BDNF and activity-dependent neuroprotective protein (ADNP) upregulation.
Published Research
Chronic Inflammatory Respiratory Syndrome (CIRS)
ModerateVIP has been studied by Ritchie Shoemaker and others in the context of chronic inflammatory response syndrome triggered by biotoxin exposure (mold illness). VIP deficiency is documented in CIRS patients, and intranasal VIP replacement has shown improvements in pulmonary artery pressure, inflammatory markers (TGF-β1, MMP-9, C4a), and quality-of-life metrics in observational studies.
Pulmonary Arterial Hypertension
ModerateVIP is a potent pulmonary vasodilator and is deficient in pulmonary arterial hypertension (PAH) lung tissue. Inhaled VIP (aviptadil) has been studied in Phase II trials for PAH, demonstrating acute reduction in pulmonary vascular resistance and mean pulmonary artery pressure. Aviptadil was also investigated for ARDS during the COVID-19 pandemic.
Autoimmune & Inflammatory Diseases
ModeratePreclinical studies demonstrate VIP efficacy in models of rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis (EAE), and type 1 diabetes. VIP shifts immune responses from inflammatory Th1/Th17 toward tolerogenic Treg profiles. These effects are mediated by induction of tolerogenic dendritic cells and expansion of regulatory T cells.
Neuroprotection & Neurodevelopment
PreclinicalVIP is critical for brain development — VIP-deficient mouse models show microcephaly and learning deficits. In adult models, VIP protects neurons against excitotoxicity, oxidative stress, and amyloid-beta toxicity. The VIP-induced neuroprotective factor ADNP (activity-dependent neuroprotective protein) has led to development of NAP/davunetide for Alzheimer's research.
Circadian Rhythm & Sleep
PreclinicalVIP neurons in the suprachiasmatic nucleus are essential for circadian clock synchronization. VIP-deficient mice show disrupted circadian rhythms, fragmented sleep, and impaired metabolic cycling. Research suggests VIP signaling integrates light-dark information with peripheral clock gene expression across tissues.
Safety Profile
VIP has been administered intravenously and via inhalation in human clinical studies for pulmonary hypertension and ARDS. Aviptadil (pharmaceutical VIP) received FDA Fast Track designation for ARDS. Reported adverse effects include transient hypotension, facial flushing, and diarrhea, consistent with its vasodilatory and secretomotor properties. Intranasal VIP for CIRS has been used in clinical practice with a favorable safety profile. As an endogenous neuropeptide with a short half-life (~2 minutes in plasma), systemic effects are self-limiting.
Handling & Storage
Reconstitute with bacteriostatic water. VIP is a 28-amino-acid peptide with moderate aqueous stability. Sensitive to temperature — do not heat. Store reconstituted solution at 2-8°C and use within 14 days. Lyophilized powder stable at -20°C for 24+ months. VIP has a very short plasma half-life (~2 minutes), which is why intranasal delivery is preferred for CNS/pulmonary targeting.
Peer-Reviewed Literature
- 1
Polypeptide with broad biological activity: isolation from small intestine
Said SI, Mutt V.
- 2
The significance of vasoactive intestinal peptide in immunomodulation
Delgado M, Pozo D, Ganea D.
- 3
Vasoactive intestinal polypeptide (VIP) corrects chronic inflammatory response syndrome (CIRS) acquired following exposure to water-damaged buildings
Shoemaker RC, House D, Ryan JC.
Health, 2013DOI - 4
Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension
Petkov V, Mosgoeller W, Ziesche R, et al.
VIP FAQ
What is VIP?
VIP (Vasoactive Intestinal Peptide) is a 28-amino-acid neuropeptide discovered in 1970 by Sami Said and Viktor Mutt. Despite its name, VIP is found far beyond the intestine — it is a widely distributed neurotransmitter and immunomodulator present in the central nervous system, lungs, immune cells, and gastrointestinal tract. It signals through VPAC1 and VPAC2 receptors to mediate vasodilation, anti-inflammatory effects, and neuroprotection.
What is VIP used for in CIRS research?
In chronic inflammatory response syndrome (CIRS), VIP levels are often depleted. Intranasal VIP replacement has been studied as a late-stage intervention after binder protocols and environmental remediation. Research shows effects on reducing pulmonary artery pressure, normalizing inflammatory markers (TGF-β1, MMP-9, C4a), and improving subjective quality of life. VIP is typically the final step in the Shoemaker CIRS treatment protocol.
How should VIP be stored?
Lyophilized VIP should be stored at -20°C for long-term stability. Once reconstituted with bacteriostatic water, store at 2-8°C and use within 14 days. VIP is temperature-sensitive — do not expose to heat. The short plasma half-life (~2 minutes) is why storage stability and reconstituted freshness are particularly important.
What is the difference between VIP and PACAP?
VIP and PACAP are members of the same peptide superfamily and share 68% sequence homology. Both activate VPAC1 and VPAC2 receptors, but PACAP also activates PAC1 (a PACAP-selective receptor). VIP is primarily studied for immunomodulation, pulmonary function, and CIRS. PACAP is more studied for neuroprotection and cognitive function. Their overlapping but distinct receptor profiles create different therapeutic research niches.
What is aviptadil?
Aviptadil is the pharmaceutical name for synthetic VIP. NeuroRx developed inhaled aviptadil (Zyesami) for ARDS and received FDA Fast Track designation during the COVID-19 pandemic for treatment of respiratory failure. It is also studied in pulmonary arterial hypertension. Aviptadil is the same 28-amino-acid sequence as endogenous VIP.
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Disclaimer: This monograph is provided for educational and research purposes only. G26x Peptides products are sold exclusively as research chemicals. They are not intended for human consumption, therapeutic use, or as dietary supplements. All research should be conducted in compliance with applicable laws and institutional review board protocols. Information presented here is sourced from published peer-reviewed literature and does not constitute medical advice.