VIP and Cardiovascular Signalling: VPAC Receptors, cAMP Pathways and Cardiac Research

VIP and Cardiovascular Research

Vasoactive intestinal peptide, or VIP, is a naturally occurring neuropeptide belonging to the secretin peptide family. It is distributed throughout the central and peripheral nervous systems and has been investigated in several physiological systems, including the cardiovascular system.

Cardiovascular research involving VIP has examined vascular tone, coronary circulation, cardiac contractility, heart-rate regulation and neurovascular signalling. These effects are primarily studied through the interaction of VIP with class B G protein-coupled receptors, particularly VPAC1 and VPAC2.

This makes VIP relevant to cardiovascular signalling research without requiring the broader and less precise description of VIP as a compound for “heart health.” The experimental question is instead how VIP receptor activation influences cardiovascular tissues under defined conditions.

VPAC1 and VPAC2 Are the Principal VIP Receptors

VIP mainly exerts its effects through two closely related receptors, VPAC1 and VPAC2. These receptors are part of the class B family of G protein-coupled receptors and are able to bind VIP with high affinity.

Another peptide which is structurally related is PACAP, as it too interacts with these receptors and has the ability to activate the PAC1 receptor. It is important to take this overlap into account when interpreting the experiments since VIP and PACAP may use the same receptor systems even though they show different preferences for those receptors.

The presence of VPAC1 and VPAC2 also differs from one tissue to another. As a result, the response seen after VIP has been exposed may depend on which receptor subtype is present in the experimental preparation.

VIP Receptor Activation and cAMP Signalling

A well-defined signalling mechanism linked with VPAC receptors is their coupling to the Gs protein.

Activating either VPAC1 or VPAC2 can cause adenylyl cyclase to be stimulated, which in turn raises the amount of cyclic adenosine monophosphate within the cell, or cAMP. The increased level of cAMP can then affect protein kinase A and other subsequent signalling processes.

This offers a useful molecular framework for the study of VIP in cardiovascular tissues; nevertheless, cAMP is not a feature that is specific to VIP. Since other receptor systems are also able to regulate intracellular cAMP, alterations in cAMP concentration should be interpreted in light of receptor-selective experiments and the use of appropriate controls.

VIP and Coronary Vascular Signalling

One main area of cardiovascular VIP research looks at coronary vascular tone.

VIP-containing nerve fibres have been found in and around the coronary vessels and in several cardiac structures. Experimental studies have examined whether endogenous VIP has a role in the regulation of coronary vascular resistance and coronary blood flow.

A study involving isolated perfused rat hearts gives a more specific example of the mechanisms at work. When VPAC1 and VPAC2 receptors were selectively activated, there was a decrease in coronary vascular resistance, and the pharmacological experiments indicated that VPAC2 signalling made an important contribution. In the same study, the role of potassium channels was examined and it was found that ion-channel activity can contribute to the vascular response.

It is for this reason that receptor-selective experiments are useful since it is not certain that determining the vascular response following VIP exposure will show which receptor subtype or intracellular pathway was responsible for it.

VIP and Cardiac Contractility

VIP research has also looked into its direct effects on the cardiac muscle.

Previous cardiovascular studies have shown the presence of VIP-containing nerve fibres in various areas of the heart, such as the atria, the ventricles, the sinoatrial node, the atrioventricular node and the intracardiac ganglia. Experimental research has been carried out to find out whether VIP signalling has an effect on cardiac contractility and chronotropic activity.

The cardiac response is not simply a matter of measuring blood flow. Contractility, heart rate, vascular resistance and autonomic signalling represent different physiological endpoints.

Separating these measurements is therefore important when interpreting VIP experiments. A change in coronary vascular resistance, for example, does not by itself establish a direct effect on myocardial contractility.

VIP and Heart-Rate Signalling

The fact that VIP-containing fibres are found around the sinoatrial and atrioventricular nodes has led to investigations into their possible role in cardiac electrical activity.

Experimental studies have looked at the changes in heart rate that occur after exposure to VIP and during autonomic stimulation. According to the literature on the cardiovascular system, VIP is regarded as one of a number of neuropeptides that take part in the autonomic regulation of the heart.

The study is especially useful when looked at in conjunction with the distribution of VIP receptors and the autonomic nerve fibres. It shows the way in which a peptide neurotransmitter can have an effect on cardiovascular tissues via both neural and receptor-mediated mechanisms.

VIP Signalling Involves More Than One Intracellular Pathway

Even though cAMP is a key element of VPAC signalling, it is by no means the only intracellular messenger that has been studied in connection with VIP.

Studies into the pharmacology of VPAC receptors have also examined signalling pathways related to calcium and phospholipase, as well as those involving adenylyl cyclase and cAMP. Research has likewise been carried out on receptor phosphorylation, internalisation, coupling to G proteins, and receptor oligomerisation.

The wider signalling structure enables one to understand why VIP gives different responses in various tissues since the experimental response can be affected by receptor abundance, accessory proteins, the intracellular signalling machinery and the cellular phenotype.

Receptor Selectivity Matters in Cardiovascular VIP Research

VPAC1 and VPAC2 are structurally related, but their distribution in different tissues and their pharmacological properties are not the same.

Receptor-selective agonists or antagonists can therefore be used to obtain information that cannot be gained from VIP exposure alone. For instance, in the isolated rat heart selective agonists for VPAC1 and VPAC2 caused measurable alterations in coronary vascular resistance, and receptor antagonists were used to examine the contribution of VPAC2 signalling.

It is with this kind of experimental design that researchers are able to progress from an observed physiological response to a more particular molecular explanation.

VIP, PACAP and Receptor Overlap

VIP is closely related to pituitary adenylate cyclase-activating polypeptide, that is PACAP; the two peptides are part of the same peptide superfamily and have a considerable degree of sequence similarity.

Their receptor pharmacology is, however, different since VIP has a high affinity for both VPAC1 and VPAC2, whereas PACAP has a high affinity for VPAC1, VPAC2 and also for PAC1; VIP has considerably lower affinity for PAC1 than PACAP.

The fact that there is an overlap has important implications for experiments involving the cardiovascular system. When a response is generally assigned to the "VIP receptor family" it may be due to different receptor subtypes according to the peptide and the experimental preparation.

VIP and Coronary Blood Flow in Experimental Models

Animal and isolated-organ models have been especially useful in the investigation of the cardiovascular effects of VIP.

Using isolated perfused heart preparations, researchers are able to control various factors such as perfusion pressure, the composition of the extracellular fluid, and peptide concentration while at the same time measuring coronary vascular resistance and other cardiac parameters. It is therefore possible for these models to help in the identification of receptor-dependent vascular mechanisms.

In vivo studies provide a more integrated physiological environment but introduce additional variables, including autonomic regulation, circulating hormones and interactions between vascular beds.

Neither model completely reproduces the complexity of human cardiovascular physiology. The appropriate interpretation therefore depends on the research question.

Measuring VIP Cardiovascular Responses

The information obtained from different experimental endpoints relates to different stages of VIP signalling.

Researchers can measure receptor expression, intracellular cAMP, coronary vascular resistance, coronary blood flow, myocardial contractility or heart rate. Molecular assays are able to examine receptor abundance and downstream signalling, whereas isolated-organ and animal models give information on integrated physiological responses.

One should not regard these endpoints as being interchangeable.

For instance, while an increased level of cAMP shows that there is intracellular signalling it does not directly prove that there has been a change in coronary vascular resistance. Similarly, a change in coronary blood flow alone does not show that the response took place via a particular VPAC receptor without further pharmacological or genetic evidence.

VIP Stability and Experimental Interpretation

VIP is a peptide of relatively small size and is susceptible to enzymatic degradation. Since its short biological half-life has been identified, this has become an important factor to take into account when studying the pharmacology of VIP.

The situation has consequences for the way experiments are designed since the concentration of peptide at the start of the experiment need not be the same as that of the intact peptide throughout the whole period of observation.

Sample handling, the results of the analysis, the length of time exposed and the degree of degradation can therefore have an effect on reproducibility.

It is important when carrying out research which involves the use of synthetic VIP to verify the peptide's identity and purity as part of setting up the experimental conditions.

What Cardiovascular VIP Research Can and Cannot Establish

There is ample evidence from published research to show that VIP signalling interacts with cardiovascular tissues and that activation of VPAC receptors can affect vascular and cardiac measurements under specific experimental conditions.

One should not turn these observations into general statements regarding 'heart health'. The cardiovascular responses depend on the receptor subtype, the distribution of the tissue, the experimental model, the concentration of the peptide, the conditions of exposure, and the endpoint being measured.

It is especially important to draw the line between research into physiology and claims regarding therapy. Just because experimental evidence shows a receptor-mediated response does not mean that a peptide of research grade is suitable for use in humans or that it can be used to prevent, diagnose or treat cardiovascular disease.

Research Use Only

Direct SARMS supplies peptide materials for use in laboratory and analytical research. The information given in this article is for scientific and educational use and relates to published research on VIP receptor pharmacology, cardiovascular signalling and experimental models.

Research-use-only materials are not intended for human or animal consumption, diagnosis, treatment, prevention or mitigation of disease. Published cardiovascular studies should not be interpreted as instructions or recommendations for using research materials.

FAQs

References

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