Vasoactive Intestinal Peptide (VIP): A 28-Residue Class B GPCR Ligand

Research summary. Vasoactive intestinal peptide (VIP) is a 28-residue endogenous neuropeptide first isolated from porcine intestine in 1970 by Said and Mutt. It is a member of the secretin/glucagon peptide superfamily and signals primarily through the class B G protein-coupled receptors VPAC1 and VPAC2 (and, with lower affinity, the related PAC1 receptor shared with PACAP). VIP is widely distributed across the gastrointestinal tract, central and peripheral nervous systems, immune cells, and pulmonary and cardiovascular tissues, and has been studied across an unusually broad range of research areas — vasodilation, smooth-muscle relaxation, immunomodulation toward Th2-skewed responses, neuroprotection, and circadian-rhythm regulation in the suprachiasmatic nucleus. Multiple VIP analogues and PACAP/VIP-receptor agents have been investigated clinically.

Molecular profile

• Sequence: HSDAVFTDNYTRLRKQMAVKKYLNSILN-NH₂
• Molecular formula: C₁₄₇H₂₃₇N₄₃O₄₃S
• Molecular weight: ~3326 g/mol
• PubChem CID: 44567960
• CAS number: 37221-79-7
• Human gene: VIP (chromosome 6q25.2)
• Class: Secretin/glucagon-superfamily neuropeptide
• Synonyms: Vasoactive intestinal polypeptide

Mechanism of action

VIP signals through three related class B GPCRs:

• VPAC1 (VIPR1). Broadly distributed (lung, intestine, T cells, brain); generally couples to Gαs and elevates cAMP. Mediates vasodilation, smooth-muscle relaxation, and many immunomodulatory effects.
• VPAC2 (VIPR2). Highly expressed in the suprachiasmatic nucleus, smooth muscle, and immune cells; central to circadian-rhythm regulation and bronchial smooth-muscle relaxation.
• PAC1. Shared with the related peptide PACAP; VIP binds with lower affinity than PACAP but contributes to neuronal effects in some contexts.
• Anti-inflammatory bias. VIP signalling on immune cells skews dendritic-cell maturation, T-cell differentiation, and macrophage activation toward tolerogenic and Th2-type profiles, with associated reductions in pro-inflammatory cytokine output.
• Short plasma half-life. Native VIP has a half-life on the order of minutes, motivating extensive analogue and formulation research.

Preclinical and clinical research highlights

Vasodilation and smooth-muscle relaxation. VIP produces vasodilation, bronchial smooth-muscle relaxation, and gastrointestinal smooth-muscle relaxation — the activity profile that gave it its name.

Pulmonary research. VIP and inhaled VIP analogues have been investigated in pulmonary arterial hypertension, asthma, and sarcoidosis research, with multiple early- and mid-stage clinical-trial programmes in pulmonary hypertension.

Inflammatory bowel disease models. Preclinical research has reported attenuated colitis severity and reduced Th1 cytokine output in murine models of IBD treated with VIP or VIP-derived peptides.

Neuroprotection and CNS research. VIP and the related peptide PACAP have been studied in models of Alzheimer's disease, Parkinson's disease, and ischemic CNS injury, with reported reductions in neuroinflammation and beta-amyloid-related markers, mediated through VPAC1/VPAC2 signalling and downstream secretion of neurotrophic factors including ADNP.

Transplant immunology. Preclinical research has examined VIP for induction of tolerogenic dendritic cells and reduction of acute-rejection markers in transplant models.

Cardiac fibrosis models. Rodent studies have reported VIP effects on cardiac extracellular-matrix remodelling, including reduced angiotensin-receptor expression, in models of cardiac fibrosis.

Circadian rhythm. VIP–VPAC2 signalling in the suprachiasmatic nucleus is essential for synchronisation of the central circadian pacemaker, and Vipr2-null and Vip-null mice show profound circadian-rhythm disruption.

Current research status

Native VIP is not FDA-approved for any indication. Inhaled and modified VIP analogues have been investigated clinically for pulmonary indications, and broader VPAC1/VPAC2 receptor pharmacology remains an active area of drug discovery. Research-grade VIP is supplied for laboratory use only.

Key takeaways for researchers

• VIP is a 28-residue endogenous neuropeptide of the secretin/glucagon superfamily that signals through VPAC1, VPAC2, and (with lower affinity) PAC1 receptors.
• Its biological profile spans vasodilation, smooth-muscle relaxation, anti-inflammatory and Th2-biased immunomodulation, neuroprotection, and circadian-rhythm regulation in the SCN.
• Multiple VIP analogues have been investigated in pulmonary indications, but no native-VIP product is currently FDA-approved.
• The very short plasma half-life of native VIP is the dominant constraint on therapeutic translation and motivates ongoing analogue research.
• Research-grade VIP is supplied for laboratory use only.

References

1. Said SI, Mutt V. Polypeptide with broad biological activity: isolation from small intestine. Science. 1970;169(3951):1217–1218.
2. Delgado M, Ganea D. Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions. Amino Acids. 2013;45(1):25–39.

---

This article is provided for educational and research purposes only. VIP is a research peptide. It is not currently FDA-approved and is not intended for human consumption, diagnosis, treatment, cure, or prevention of any disease or condition. All work involving this peptide should be conducted by qualified personnel within an appropriate research setting and in compliance with applicable institutional and regulatory requirements.