VIP

Vasoactive Intestinal Peptide (VIP) is a pleiotropic growth factor and vasodilator upregulated by acute exercise that activates VPAC receptors to potentiate hippocampal synaptic transmission and promote myelin regeneration PMID 39352588PMID 35283168. Its therapeutic potential lies in its ability to reduce neuroinflammation and reconstruct intestinal function following spinal cord injury, while also potentially supporting cognitive plasticity through the modulation of NMDA receptor currents PMID 39352588PMID 35283168.

• Synaptic Plasticity and LTP: In the brain, particularly the hippocampus, VIP activates VPAC1 and VPAC2 receptors on CA1 pyramidal cells. VPAC1 activates the PLC/IP3 and PLC/PKC signaling pathways, while VPAC2 induces the cAMP/PKA pathway. These cascades enhance synaptic transmission by increasing NMDA receptor currents, a process essential for Long-Term Potentiation (LTP) PMID 35283168.
• Cellular Growth and Regeneration: VIP affects cell proliferation, differentiation, survival, and maturation. It mediates neuroprotective functions, promotes myelin regeneration, and reduces inflammatory responses within the nervous system PMID 39352588.
• Systemic Physiology: Outside the CNS, VIP acts as a potent vasodilator and a gastrointestinal hormone that regulates intestinal peristalsis and colon motility PMID 39352588PMID 35283168).

VIP is classified as an exerkine because its circulating levels are significantly modulated by physical activity, with exercise serving as a non-invasive means to enhance its expression.

• Acute Exercise Response: Acute bouts of exercise - including exhaustion protocols, submaximal exercise, and low-intensity long-duration exercise - induce significant increases in plasma VIP levels. This rise is attributed partly to the overflow of the peptide at skeletal muscle blood vessels to facilitate vasodilation PMID 39352588PMID 35283168.
• Chronic Exercise Response: Long-term physical activity was not shown to upregulate VIP, suggesting that the response may vary based on the timescale of exercise PMID 35283168.

• Spinal Cord Injury (SCI) & Bowel Dysfunction: Following SCI, VIP expression in the colon decreases, contributing to neurogenic bowel dysfunction (NBD) (e.g., constipation, incontinence). Enhancing VIP levels—potentially through exercise or electrical stimulation—can promote colon motility and help reconstruct intestinal function PMID 39352588.
• Neuroprotection and Myelin Repair: VIP mediates multiple neuroprotective functions, including the promotion of myelin regeneration and the reduction of inflammation, making it a relevant factor for neural repair strategies PMID 39352588.
• Cognitive Decline: By potentiating LTP-related pathways (cAMP/PKA and PKC) in the hippocampus, VIP targets synaptic plasticity mechanisms that are often compromised in cognitive decline, although direct evidence linking exercise-induced VIP to improved human cognition remains an area for further study PMID 35283168.

1. Respiratory and Infectious Diseases

• COVID-19 and Viral Infections: VIP (Aviptadil) has been explored for critical COVID-19 respiratory failure, showing potential to improve survival likelihood at 60 days, although some primary endpoints regarding respiratory failure freedom were not statistically met PMID 36044317. VIP downregulates SARS-CoV-2 entry receptors (ACE2 and TMPRSS2) and upregulates ADAM10, suggesting a mechanism to hamper viral entry PMID 40141308. It is considered a broad potential target for antiviral therapy PMID 35770640.
• Lung Injury and Inflammation: In models of acute lung injury (ALI), VIP signaling pathways (VIP/cAMP/PKA) are crucial for the protective effects of various compounds, such as purple sweet potato polysaccharide and pseudoephedrine/emodin, which regulate macrophage polarization and reduce inflammation PMID 39522908PMID 35123524.
• Developmental Disorders: In congenital diaphragmatic hernia models, the VIP analog Aviptadil restored downregulated VIP levels and attenuated vascular remodeling and alveolar dysplasia PMID 41342973. However, bacterial pathogens like Bordetella species may manipulate VIP/VPAC2 signaling to persist in the respiratory tract, suggesting VPAC2 antagonists could promote bacterial clearance PMID 37065208.

2. Neurological and Psychiatric Applications

• Neuroprotection: Gene therapy using lentiviral vectors encoding VIP (LentiVIP) protects microglia and neurons from degeneration in cellular Parkinson's disease models PMID 38382910. VIP also mitigates pesticide-induced neuroinflammation in microglial cells PMID 35199308 and modulates microglial function in multiple sclerosis (MS) to promote myelin repair PMID 35563181PMID 39201536.
• Stroke: In ischemic stroke treatment, VIP pathway activation helps maintain blood-brain barrier integrity PMID 40102879. Chemogenetic activation of VIP interneurons has been shown to improve sensory response and functional recovery after stroke in murine models PMID 34671051.
• Pain and Migraine: Activation of VIP interneurons in the prefrontal cortex can ameliorate neuropathic pain aversiveness PMID 36103825. Conversely, in migraine, VIP levels are elevated PMID 40458768, and inhibiting the related PACAP/VIP signaling pathway is a therapeutic strategy; for instance, the antibody Lu AG09222 inhibits vasodilation associated with these peptides PMID 37231350.
• Cognition and Mental Health: VIP interneurons are implicated in attention deficits associated with Fragile X Syndrome, presenting a target for improving attention PMID 37816596. Additionally, VIPR2 antagonists are being developed as potential treatments for schizophrenia PMID 36990792.

3. Oncology: Agonism vs. Antagonism

• Antagonism for Immunotherapy: In pancreatic ductal adenocarcinoma (PDAC) and melanoma, VIP signaling acts as an immune checkpoint. Using VIP receptor antagonists (e.g., ANT308) or inhibiting VIP signaling enhances T-cell function and response to immune checkpoint therapies, reducing growth of tumor metastases PMID 36302761PMID 40482913.
• Receptor Targeting: VIP receptors are overexpressed in certain cancers, allowing for targeted drug delivery. VIP-grafted nanoplatforms have successfully targeted breast cancer cells PMID 33819623 and fibroblast-like synoviocytes in rheumatoid arthritis PMID 41330501.
• Tumor Promotion: Dimerization of the VIP receptor VIPR2 has been linked to breast cancer progression, making the monomer-dimer interface a potential therapeutic target PMID 40203889.

4. Metabolic, Autoimmune, and Ocular Disorders

• Diabetes: VIP and specific VPAC2 receptor agonists are being investigated for Type 2 diabetes due to their ability to stimulate glucose-dependent insulin secretion PMID 36204104PMID 36642263. LentiVIP gene therapy has also shown promise in suppressing inflammation and augmenting beta-cell proliferation in Type 1 diabetes models PMID 32733091.
• Inflammation and Bone Loss: VIP exhibits immunoregulatory properties in autoimmune arthritis models PMID 34335612. A stable VIP derivative, Stearyl-Norleucine-VIP, demonstrated potential in preventing inflammation-induced osteolysis and bone destruction PMID 34025407.
• Ocular Health: VIP and its receptor VIPR2 are emerging as key modulators in myopia pathogenesis and potential therapeutic targets for ocular growth regulation PMID 41421442. Additionally, a combination of Thymosin beta-4 and VIP protects corneal epithelial cells from hyperglycemia-induced damage PMID 37998149.

5. Pharmacology and Drug Design

• Recent advancements include the identification of existing drugs like Ticagrelor as allosteric modulators of VIP receptors PMID 34867774 and the development of fluorescently labeled VIP analogs to study receptor internalization and biased agonism, aiding future drug design PMID 36654758PMID 35897648.