Vasoactive Intestinal Peptide (VIP)

What it is

VIP is a 28-amino acid neuropeptide originally isolated from porcine duodenum and subsequently found throughout the central and peripheral nervous systems, gastrointestinal tract, and various endocrine and immune cells. It belongs to the secretin/glucagon peptide family (PMID 2698176, PMID 7209387). VIP exerts its effects primarily by binding to G-protein-coupled receptors—VPAC1, VPAC2, CRTH2, and PAC1—expressed on numerous cell types including immune cells (eosinophils, mast cells, neutrophils, lymphocytes), cardiac tissue, smooth muscle, and neurons (PMID 28964637, PMID 11121793). Receptor binding activates adenylyl cyclase, elevating intracellular cAMP, which mediates downstream signaling cascades (PMID 18172612, PMID 2852963). General physiological effects include vasodilation, smooth muscle relaxation, anti-inflammatory actions, regulation of gastric motility, hormonal secretion, and cell proliferation. VIP is rapidly degraded in vivo, with metabolic clearance occurring principally in the liver and kidneys. On a molar basis, VIP is reported to be 50–100 times more potent than acetylcholine as a vasodilator. VIP also functions as a neurotransmitter/neuromodulator in circadian rhythm regulation via the suprachiasmatic nucleus (SCN), where approximately 10% of SCN neurons express VIP.

Class: Neuropeptide / Peptide Hormone (secretin/glucagon family)

What it's studied for

• Cardiovascular effects (vasodilation, coronary blood flow, cardiac contractility, heart rate regulation) Mixed
  • VIP administered intracoronary or intravenously increases epicardial coronary artery cross-sectional area, decreases coronary vascular resistance, and increases coronary blood flow in both research animals and humans. VIP has a positive inotropic effect on cardiac muscle, augments developed isometric force, and increas PMID 11121793 Henning RJ, Sawmiller DR. Cardiovascular research (2001)
• Immunomodulation and anti-inflammatory actions Mixed
  • VIP modulates a variety of immune responses including T cell recognition, antibody production, and maturation of specific effector cell populations; effects are generally but not always mediated through cAMP generation in lymphocytes and accessory cells. VIP has potential protective effects against tissue damage in inf PMID 8790778 Bellinger DL et al. Advances in neuroimmunology (1996)
  • VIP mediates immunological functions through VPAC-1, VPAC-2, CRTH2, and PAC1 receptors on eosinophils, mast cells, neutrophils, and lymphocytes. Review discusses VIP's role in pathogenesis of allergic diseases including asthma, allergic rhinitis, and atopic dermatitis. PMID 28964637 Verma AK et al. Cytokine & growth factor reviews (2017)
  • In cultured rat Schwann cells and sciatic nerve explants, VIP inhibited the release of pro-inflammatory cytokines and promoted myelin gene expression, suggesting roles in peripheral nerve remyelination and inflammatory regulation after injury. PMID 31920495 Woodley PK et al. Frontiers in neuroscience (2019)
• Circadian rhythm regulation via suprachiasmatic nucleus (SCN) Animal studies only
  • Approximately 10% of SCN neurons express VIP. High-frequency (but not low-frequency) VIP neuron stimulation shifted gene expression rhythms in vitro via VIP signaling. In vivo, high-frequency VIP neuron activation rapidly entrained circadian locomotor rhythms in mice. PMID 30017392 Mazuski C et al. Neuron (2018)
  • Homozygous Vip-tTA knock-in mice (complete VIP absence) showed impaired circadian behavioral rhythms—attenuated rhythmicity and shortened circadian period—similar to VIP knockout mice. PMID 35592033 Peng Y et al. Frontiers in physiology (2022)
  • Ablation of VIP SCN neurons in adult mice caused shortened circadian period, more variable activity onsets, decreased duration of daily activity, and severely dampened corticosterone rhythms. Neonatal VIP SCN neuron deletion dramatically reduced circadian gene expression, mimicking global VIP/VIPR2 deletion. PMID 32536240 Mazuski C et al. Journal of biological rhythms (2020)
• Bronchodilation / airway smooth muscle relaxation Human observational
  • In human bronchi in vitro, VIP and PHM caused dose-dependent relaxation approximately 50-fold more potent than isoproterenol. VIP is proposed as a possible neurotransmitter in nonadrenergic inhibitory nerves in human airways. PMID 3781947 Palmer JB et al. Journal of applied physiology (1986)
  • VIP antagonists ([4-Cl-D-Phe6,Leu17]-VIP and [Ac-Tyr1,D-Phe2]-GRF(1-29)-NH2) at 10^-8 M significantly enhanced contractions evoked by electrical field stimulation in human bronchus, suggesting that endogenous VIP suppresses acetylcholine release from vagus nerve terminals. PMID 8201830 Aizawa H et al. Lung (1994)
• Cancer cell biology (tumor imaging, growth stimulation, receptor targeting) Mixed
  • VIP causes increased proliferation of human breast and lung cancer cells in vitro, elevates cAMP, and increases expression of c-fos, c-jun, c-myc, and VEGF. VIPhybrid (synthetic VPAC1 antagonist) inhibits basal growth of lung cancer cells in vitro and tumors in vivo. VIP has been radiolabeled with 123I, 18F, and 99mTc PMID 12576099 Moody TW et al. Peptides (2003)
  • VIP-1 receptor mRNA detected in 28 human ductal pancreatic adenocarcinomas and seven secretin-responsive cell lines. 100 pM VIP (but not 1 µM) stimulated significant in vitro growth of VIP-1 receptor-bearing Capan-2 cells in the presence and absence of serum. PMID 9108448 Jiang S et al. Cancer research (1997)
  • VIP receptors (predominantly VPAC1) are overexpressed in MNU-induced rat breast cancer tissue compared to normal tissue, paralleling findings in human breast cancer, supporting MNU-rat model for studying VIP-receptor-mediated breast cancer targeting. PMID 11245339 Dagar S et al. Breast cancer research and treatment (2001)
• Nociception modulation (spinal cord, peripheral nervous system) Animal studies only
  • Intrathecal injection of aqueous VIP in anesthetized rats evoked significant bimodal, concentration-dependent response: early antinociception followed by hyperalgesia during noxious skin heating. Alpha-helix VIP (in phospholipid micelles) produced qualitatively similar but kinetically distinct responses. PMID 12860207 Yeomans DC et al. Peptides (2003)
• Urinary bladder function and inflammation Animal studies only
  • VIP(-/-) mice exhibited increased bladder mass, altered voiding patterns, increased urea permeability, and exaggerated/prolonged bladder hyperreflexia and somatic sensitivity following cyclophosphamide-induced bladder inflammation compared to wild-type mice, indicating VIP's role as an endogenous anti-inflammatory agen PMID 18561033 Studeny S et al. Journal of molecular neuroscience (2008)
• Hippocampal synaptic plasticity and cognition / epilepsy Animal studies only
  • Review: In the hippocampus, VIP regulates GABAergic transmission and pyramidal cell activity through VIP-containing basket cells and interneuron-selective interneurons. VIP promotes disinhibition via VPAC1 receptors or enhances pyramidal cell excitability via VPAC2 receptors, controlling LTP and LTD. VIP receptor ligan PMID 32595454 Cunha-Reis D, Caulino-Rocha A. Frontiers in cellular neuroscience (2020)
• Peripheral nerve regeneration Animal studies only
  • VPAC1, VPAC2, and PAC1 are up-regulated in the mouse distal nerve following peripheral nerve injury and highly expressed in Schwann cells and macrophages. VIP promoted myelin gene expression in cultured rat Schwann cells and inhibited pro-inflammatory cytokine release in Schwann cells and sciatic nerve explants. PMID 31920495 Woodley PK et al. Frontiers in neuroscience (2019)
• Antimicrobial activity (recombinant VIP expressed in Pichia pastoris) In vitro only
  • Recombinant VIP expressed in Pichia pastoris showed antibacterial activity against E. coli ATCC25922 (MIC 8 mmol/L) and S. aureus ATCC25923 (MIC 16 mmol/L) via membrane disruption, with minimal cytotoxicity to normal cells NCM460 and IPEC-J2, and little hemolytic activity to SD rat erythrocytes. PMID 29943546 Qiao X et al. Chinese journal of biotechnology (2018)
• Ovarian immune homeostasis and prevention of premature ovarian aging Animal studies only
  • Young VIP KO mice showed aberrant ovarian morphology with increased atretic follicles, decreased ovarian reserve, reduced vascularization, increased collagen deposition, elevated ROS and IL-1β levels, and predominant foamy macrophages indicating premature aging, demonstrating VIP's role in ovarian immune homeostasis. PMID 39894337 Castagnola L et al. Molecular and cellular endocrinology (2025)
• Placental glucose transport and fetal growth Animal studies only
  • VIP-deficient placentas paradoxically showed higher glucose uptake and higher GLUT1 and mTOR gene expression vs. VIP+/+ placentas. Fetal weight was reduced in association with placental VIP deficiency (normal maternal background). VIP-deficient pregnancy is proposed as a model for fetal growth restriction. PMID 34186168 Merech F et al. BBA Molecular Basis of Disease (2021)
• Glioblastoma migration and invasion inhibition Animal studies only
  • VIP and PACAP-38 significantly reduced C6 rat GBM cell invasion in ex vivo rat brain parenchyma and C6/U87 human GBM cell migration in vitro. A VIP receptor antagonist (VIP10-28) increased invasion. Effects were mediated through PKA-dependent blockade of PI3K/Akt and SHH/GLI1 pathways. PMID 30669581 Bensalma S et al. Cancers (2019)
• Allergic asthma (VIP-based drug delivery system) Animal studies only
  • In asthmatic mice, VIP-MapA-α-alumina (MAPA-VIP) delivery system reduced eosinophil percentage, IgE, IL-4, IL-5, IL-13, ROS levels, GATA3 and MUC5AC gene expression, goblet cell hyperplasia, and peribronchial/perivascular inflammation. VIP-MapA showed stronger effects than VIP alone. PMID 37143998 Jia W, Yang D. Postepy dermatologii i alergologii (2023)
• Cluster headache (VIP infusion provocation) Human observational
  • VIP infusion provoked cluster headache attacks in individuals with episodic and chronic cluster headache. Plasma VIP levels did not significantly change during PACAP38- or VIP-induced attacks versus baseline, suggesting cluster headache induction is not associated with changes in circulating VIP. PMID 37143998 Deligianni C et al. Frontiers in neurology (2023)
• Salivary VIP as biomarker of acute stress Human observational
  • A brief, intense exercise (lasting minutes) significantly increased salivary VIP (alongside cortisol, DHEA, and amylase) in humans. A less rigorous exercise did not elicit significant increases, and a longer intense exercise (hours) elevated only cortisol. PMID 23994551 Ventre G et al. Peptides (2013)
• Skin inflammatory conditions (eczema, psoriasis) Human observational
  • VIP concentrations were elevated in skin biopsies from patients with eczema and psoriasis compared to controls, while substance P and somatostatin levels did not differ. VIP was not elevated in axillary hyperhidrosis. PMID 1712221 Anand P et al. British journal of dermatology (1991)
• Circulating VIP elevation in uraemia and liver cirrhosis Human observational
  • Peripheral venous VIP was significantly elevated in patients with decreased kidney function (median 15.0 pmol/L vs. 6.0 pmol/L in controls; P<0.0001) and slightly elevated in patients with liver cirrhosis (median 7.0 pmol/L; P<0.01). Renal and hepatic VIP extraction was demonstrated, implicating both organs in VIP biod PMID 3089817 Henriksen JH et al. European journal of clinical investigation (1986)
• CNS trophic and neuroprotective effects (neurogenesis, embryonic development) Animal studies only
  • VIP stimulates proliferation and differentiation of brain neurons during neurogenesis in embryonic mouse spinal cord cultures, increases neuronal survival and ADNF secretion from astroglial cells. VIP is described as an integrative regulator of brain growth and development. PMID 12576099 Moody TW et al. Peptides (2003)

Community-reported dosing

Tier key: Research = PMID-cited study · [C] = scraped community source · [S] = model-synthesized from aggregate community reports (softer evidence). How we source.

Safety signals

• Poor metabolic stability: VIP is rapidly degraded in vivo, primarily by the liver and kidneys; reduced renal and hepatic clearance in uraemia and liver cirrhosis leads to significantly elevated plasma VIP levels. PMID 18172612
• Elevated plasma VIP (median 15.0 pmol/L) in patients with decreased kidney function (uraemia), significantly higher than controls (median 6.0 pmol/L), potentially due to decreased renal and hepatic biodegradation and/or increased neuronal release. PMID 3089817
• Biphasic nociceptive response: intrathecal VIP in rats produced early antinociception followed by hyperalgesia in a concentration-dependent manner; alpha-helix VIP had a faster decay of antinociception at low rates of skin heating. PMID 12860207
• VIP stimulates in vitro growth of VIP-1 receptor-bearing pancreatic adenocarcinoma cells (Capan-2) at 100 pM; VIP receptors are overexpressed in multiple human cancer types including breast, lung, and pancreatic adenocarcinoma. PMID 9108448
• VIP increases proliferation of human breast and lung cancer cells in vitro and elevates expression of c-fos, c-jun, c-myc, and VEGF; these trophic effects on cancer cells are reversed by a VPAC1 antagonist. PMID 12576099
• Tyrosine nitration of VIP (at Tyr10 and Tyr22) in inflammatory conditions reduces alpha-helix content and significantly decreases cAMP secretion (p<0.01 vs. wild-type VIP at 10 nM), suggesting VIP may have attenuated activity in inflammatory/autoimmune disease environments. PMID 37481062
• VIP infusion provoked cluster headache attacks in patients with episodic and chronic cluster headache; plasma VIP levels did not significantly change during induced attacks. PMID 37143998

Contraindications

• Use in patients with VIP-receptor-overexpressing cancers (e.g., breast, lung, pancreatic adenocarcinoma) may be contraindicated given evidence that VIP stimulates tumor cell growth in vitro via VPAC1 receptors. PMID 12576099
• Use in patients with severe renal impairment (uraemia) or hepatic impairment (liver cirrhosis) may result in significantly elevated plasma VIP levels due to reduced biodegradation, with unpredictable physiological consequences. PMID 3089817
• Individuals with cluster headache (episodic active phase or chronic) may be at risk of headache attack induction following VIP infusion. PMID 37143998