VIP

Vasoactive Intestinal Peptide (VIP)

Vasoactive Intestinal Peptide (VIP), alternatively known as vasoactive intestinal polypeptide, is a naturally occurring short peptide hormone found in the gut, pancreas, and central nervous system of most vertebrate species, including humans. Its diverse functions are mediated through interaction with class II G protein-coupled receptors (GPCRs), specifically VPAC1 and VPAC2.

VIP plays a crucial role as both a neuromodulator and a hormone, exhibiting a broad range of physiological effects:

• Metabolic Regulation: Promotes the breakdown of glycogen (glycogenolysis) in the liver and muscle tissue.
• Cardiovascular System: Acts as a potent vasodilator, reducing systemic blood pressure, and enhances cardiac muscle contraction by increasing both heart rate and contractile strength.
• Gastrointestinal (GI) Tract: Induces the relaxation of smooth muscles throughout the GI tract and stimulates the secretion of water and electrolytes in various GI regions, influencing motility and secretion.
• Endocrine and Exocrine Function: Regulates prolactin secretion and influences vaginal lubrication.
• Neuroprotection: Shields neurons from damage induced by ischemia and oxidative stress.
• Immune System: Modulates autonomic nervous system activity and exhibits profound anti-inflammatory and anti-fibrotic properties across multiple organs.
• Circadian Rhythm: Assists in synchronizing the central nervous system, particularly neurons within the suprachiasmatic nucleus (SCN), with environmental light cues to regulate the body’s circadian rhythms.

These varied roles have made VIP the subject of extensive scientific investigation, with one of the most significant areas of research focusing on its demonstrated ability to mitigate inflammation and fibrosis in various organ systems.

Vasoactive Intestinal Peptide (VIP) 10mg Overview

Vasoactive Intestinal Peptide (VIP) functions primarily by activating the VPAC1 and VPAC2 receptors, which are G protein-coupled receptors widely distributed across various tissues. Receptor activation initiates an intracellular signaling cascade that elevates levels of cyclic adenosine monophosphate (cAMP). This increase in cAMP mediates several downstream effects, notably promoting smooth muscle relaxation, leading to improved blood flow and vasodilation.

VIP is a key focus in research due to its capacity to regulate the immune response. Studies suggest it achieves this by suppressing the production of pro-inflammatory cytokines and modulating general immune signaling pathways. It has been extensively explored in research models concerning:

• Pulmonary Diseases: For its immunoregulatory role in conditions like pulmonary fibrosis and asthma.
• Inflammatory Bowel Disorders (IBD): Investigated for its ability to stabilize the intestinal barrier and reduce inflammation.
• Neurological Conditions: Studied for its neuroprotective and anti-inflammatory roles within the central nervous system.

Additionally, VIP is a significant regulator of other core physiological processes, including endocrine function, gastrointestinal motility, and the synchronization of circadian rhythms.

Vasoactive Intestinal Peptide (VIP) Structure

Vasoactive Intestinal Peptide (VIP) is a single-chain polypeptide composed of 28 amino acid residues. It belongs to the glucagon/secretin peptide superfamily, sharing structural and sequence homology with other neuroendocrine peptides like pituitary adenylate cyclase-activating polypeptide (PACAP), secretin, and glucagon.

The primary structure of Vasoactive Intestinal Peptide (Porcine, Bovine, Human) is:

• H-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

The formula for the molecular structure is: C130H215N43O37S

The molecular weight of VIP is approximately 3325.82 g/mol. The peptide is synthesized as a pro-hormone and then enzymatically cleaved to its active form, which is characterized by an N-terminal histidine and an amidated C-terminus. This amidation (indicated by -NH2) is critical for its biological activity and receptor binding affinity.

Vasoactive Intestinal Peptide (VIP) Research

VIP research spans several major disease areas, highlighting its broad therapeutic potential as an immunomodulator and tissue-protective agent.

Bowel Inflammation

VIP is produced by several sources, including immune nerve fibers in the central, peripheral, and cardiovascular systems, as well as by immune cells themselves. This localized production underscores its role in immune regulation. VIP primarily promotes Th2-type immune responses, which are typically associated with the suppression of inflammation and the calming of the immune system. This property makes VIP and its analogues subjects of extensive study as potential modulators of inflammation in conditions such as intestinal disorders, cardiovascular diseases, and neuroinflammatory conditions.

In the context of Inflammatory Bowel Diseases (IBDs), such as Crohn’s disease and ulcerative colitis, VIP has been shown to:

1. Enhance Intestinal Barrier Stability: VIP promotes the integrity of the intestinal epithelial barrier, which is often compromised in IBD. A compromised barrier allows antigens to pass easily, triggering a significant inflammatory reaction. By enhancing barrier integrity, VIP may help limit antigen exposure to immune cells, potentially preventing a critical early event in IBD pathogenesis.
2. Lessen Th1-Driven Inflammation: VIP stimulates T cells to produce interleukin-10 (IL-10), a potent anti-inflammatory cytokine. By shifting the immune balance away from pro-inflammatory Th1 responses, VIP can directly counteract a major contributing pathway to IBD pathology.

VIP in Lung Function

VIP influences pulmonary physiology through at least two primary mechanisms, particularly in models of inflammatory lung disease:

• Modulation of Vascular Remodeling and Fibrosis: VIP appears to suppress the NFAT peptide—a regulator that typically activates T cells and increases inflammatory activity. This suppression is thought to be key in regulating T-cell-mediated inflammation in the lungs. Crucially, NFAT suppression may play a significant role in preventing pulmonary fibrosis, the severe, end-stage scarring seen in diseases like COPD and sarcoidosis. Thus, VIP is being explored for its potential to prevent progressive, fatal lung damage.
• Inhibition of Smooth Muscle Proliferation: VIP has been found to inhibit the excessive growth of smooth muscle cells in lung tissue. Since smooth muscle proliferation is a hallmark of chronic lung inflammation (e.g., in uncontrolled bronchial asthma), VIP’s ability to limit this process suggests a protective role against long-term airway remodeling associated with severe asthma.

VIP in Transplants

The core challenge in organ transplantation is the rejection of the transplanted organ by the recipient’s immune system, often managed with broad-spectrum anti-inflammatory drugs that carry risks of infection and fibrosis.

Recent VIP research has focused on its influence on Dendritic Cells (DCs), which are critical regulators of the immune response responsible for identifying antigens and activating immune defenses. VIP’s effects include:

• Reduced DC Proliferation and Activation: By reducing the activity of DCs, VIP helps prevent immune responses from being fully initiated.
• Tolerance Promotion: VIP appears to preferentially support DCs associated with tolerogenic antigens, meaning it selectively suppresses the DCs that would trigger autoimmune or rejection reactions.

These effects position VIP as a promising candidate for an immunomodulatory therapy to reduce transplant rejection, potentially offering a better side-effect profile than current broad-spectrum treatments.

VIP as a Neuroprotectant

In the Central Nervous System (CNS), VIP acts as a neurotransmitter, a neurotrophic/neurogenic factor, and a potent anti-inflammatory/neuroprotective agent.

• Blood-Brain Barrier (BBB) Integrity: Similar to its GI function, VIP helps maintain the integrity of the blood-brain barrier (BBB), the crucial interface separating circulating blood from neural tissue. BBB dysfunction is implicated in several neurological disorders, including multiple sclerosis, encephalomyelitis, and stroke.
• Neurodegenerative Disease: Research indicates that VIP can modulate the buildup of beta-amyloid in animal models of Alzheimer’s disease. It also exerts significant neuroprotective effects in Parkinson’s disease by mitigating inflammation and shifting the immune response from pro-inflammatory Th1 to anti-inflammatory Th2 activity.
• Myelination and White Matter: VIP has been shown to reduce excitotoxic white matter damage and promote neuronal fatty acid myelination, suggesting a direct role in preserving neuronal integrity and function.

Cardiac Fibrosis

Cardiac fibrosis, the final stage of many heart diseases, leads to severe complications, including reduced contractility, valve dysfunction, and abnormal electrical conduction. It often necessitates heart transplantation. While traditional treatments slow progression, complete reversal of existing fibrosis remains rare.

Recent animal studies suggest that VIP may possess the unique ability to not only inhibit fibrosis progression but also to promote scar regression. This effect is strongly linked to a significant reduction in the expression of angiotensinogen and angiotensin receptor type 1a. This mechanism aligns with the known benefits of ACE inhibitors and ARBs, which are first-line treatments for slowing cardiac remodeling and fibrosis.

Vasoactive Intestinal Peptide and COVID-19

A significant contemporary application of VIP research involves its synthetic analogue, aviptadil (RLF-100), which has been studied for its potential to mitigate lung complications in severe COVID-19 cases. Similar to natural VIP, aviptadil exhibits powerful anti-inflammatory properties by suppressing pro-inflammatory cytokine production.

In the lungs, this mechanism is believed to:

• Protect Alveolar Cells: Shield type II alveolar cells, which are essential for oxygen exchange, from inflammatory damage.
• Inhibit Viral Entry: Preclinical data suggests aviptadil may also help prevent the SARS-CoV-2 virus from entering and infecting these crucial cells.

Clinical trials have been conducted to evaluate aviptadil's efficacy in treating severe COVID-19 and preventing associated respiratory failure.

Vasoactive Intestinal Peptide (VIP) Summary of Key Research Findings

This table summarizes the key therapeutic targets and mechanisms of action for VIP as supported by scientific literature:

Target Condition

Primary Mechanism of Action

Observed Effect in Research Models

Inflammatory Bowel Disease (IBD)

Promotes Th2 immune response; enhances intestinal barrier integrity; stimulates IL-10 production.

Reduced inflammation; stabilization of the gut barrier.

Pulmonary Fibrosis/Asthma

Suppresses NFAT peptide; inhibits smooth muscle cell proliferation.

Prevention of pulmonary fibrosis; mitigation of airway remodeling.

Organ Transplantation

Reduces Dendritic Cell (DC) proliferation/activation; supports tolerogenic DCs.

Potential for reduced organ rejection with fewer side effects.

Neurodegenerative Disorders

Supports Blood-Brain Barrier (BBB); shifts Th1 to Th2 immune response.

Neuroprotection; mitigation of beta-amyloid buildup and white matter damage.

Cardiac Fibrosis

Reduces angiotensinogen and angiotensin receptor type 1a expression.

Inhibition of fibrosis progression; potential promotion of scar regression.

Storage and Handling

The stability of Vasoactive Intestinal Peptide (VIP) is crucial for the accuracy and reliability of research. Proper storage and handling protocols are essential to prevent degradation, contamination, and loss of biological activity.

Storage Instructions

All products are processed via lyophilization (freeze-drying), a specialized dehydration method that preserves stability. The lyophilized peptide is a stable, white crystalline powder.

Storage Duration

Recommended Conditions

Key Considerations

Short-Term (Days to Months)

Refrigeration below 4°C (39°F).

Lyophilized peptides are stable at room temperature for several weeks, but refrigeration is preferred.

Long-Term (Months to Years)

Freezer at -80°C (-112°F).

Optimizes stability; minimizes structural degradation.

After Reconstitution

Refrigeration below 4°C (39°F).

Stable for up to 30 days after mixing with bacteriostatic water.

Best Practices For Storing Peptides

• Minimize Freeze-Thaw Cycles: Repeated temperature fluctuations accelerate peptide degradation. It is highly recommended to aliquot the total quantity of the peptide into smaller, single-use portions immediately upon receipt.
• Avoid Frost-Free Freezers: These units undergo temperature variations during defrosting cycles, which can compromise peptide stability. Use a static or laboratory-grade freezer for long-term storage.
• Protect from Light: Store peptides in a dark environment or in light-shielded containers, as light exposure can induce structural changes.

Preventing Oxidation and Moisture Contamination

VIP must be protected from air and moisture, especially if it were to contain cysteine (C), methionine (M), or tryptophan (W) residues, which are highly sensitive to oxidation.

• Temperature Acclimation: To prevent moisture condensation (frost/dew) on the cold peptide, always allow the vial to reach room temperature before opening it after removal from the freezer.
• Minimize Air Exposure: Keep the peptide container closed as much as possible. After removing the required amount, promptly reseal the vial. Storing the remaining peptide under a dry, inert gas atmosphere (such as argon or nitrogen) can further prevent oxidation.

Storing Peptides In Solution

Peptide solutions have a significantly shorter shelf life and are more prone to bacterial degradation than their lyophilized counterparts.

• Solvent Selection: If storage in solution is necessary, use sterile buffers with a recommended pH between 5 and 6.
• Aliquoting: Divide the solution into small aliquots prior to freezing to minimize freeze-thaw cycles.
• Stability: Most peptide solutions remain stable under refrigeration at 4°C (39°F) for up to 30 days. For longer solution storage, freezing is required.

Peptide Storage Containers

Containers must be durable, clean, and chemically inert. High-quality glass vials offer the best overall characteristics (clarity, stability, and chemical resistance) for peptide storage. Plastic vials (polystyrene or polypropylene) are also suitable, particularly for shipping, but glass is generally preferred for long-term integrity.

Reference Citations

Said SI, Mutt V. Polypeptide with broad biological activity: isolation from small intestine. Science. 1970;169(3951):1217–1218.

Laburthe M, Couvineau A. Molecular pharmacology and structure of VPAC receptors for VIP and PACAP. Regul Pept. 2002;108(2-3):165-173.

Ganea D, Delgado M. The neuropeptides VIP/PACAP and T cells: inhibitors or activators? Curr Pharm Des. 2003;9(12):997-1004.

Harmar AJ, et al. Pharmacology and functions of receptors for VIP and PACAP. Br J Pharmacol. 2012;166(1):4-17.

Vaudry D, et al. Pituitary adenylate cyclase-activating polypeptide and VIP: neuroprotective peptides. Trends Neurosci. 2009;32(12):728-735.

Delgado M, et al. Vasoactive intestinal peptide and the immune system. Endocr Rev. 2004;25(5): 649-685.

Said SI. Vasoactive intestinal peptide in the lung. Ann NY Acad Sci. 1991;629:158-172.

Groneberg DA, et al. Role of VIP in airway smooth muscle function. Eur J Pharmacol. 2001;424(1):21-29.

Gozes I, et al. Neuroprotective peptide activity of VIP and derivatives. J Mol Neurosci. 2003;20(3):273-285.

Martinez C, et al. VIP and immune tolerance in inflammatory bowel disease models. Gut. 1999;45(5): 672-678.