Glucagon-like peptide-1 (GLP-1) signalling may help to restore coronary microvascular blood flow after ischaemia through a potential brain-gut-heart pathway that could be targeted to reduce cardiac damage following a myocardial infarction, according to a new study.

Even when a blocked coronary artery is reopened during treatment for myocardial infarction, blood flow does not always fully return to the heart’s smallest vessels. This complication – known as the ‘no-reflow’ phenomenon – occurs in up to 50% of patients and is linked with poorer heart function, larger infarcts and increased mortality.

Building on previous research, a new study led by the University of Bristol and University College London (UCL) and published in the journal Nature Communications, examined the mechanisms behind this process. It investigated whether GLP-1 signalling could enhance blood flow in the coronary microcirculation after cardiac ischaemia by relaxing pericytes through activation of adenosine triphosphate-sensitive potassium (KATP) channels.

Several experimental approaches were combined, including rodent models of myocardial ischaemia and reperfusion, imaging of perfused cardiac tissue and studies of cultured human cardiac pericytes.

In the animal experiments, myocardial ischaemia was induced by temporarily blocking a coronary artery and then restoring blood flow. The research team also assessed remote ischaemic preconditioning in which brief periods of reduced blood flow to a limb trigger protective signals that can minimise damage to the heart.

Pericyte contraction drives capillary obstruction

Coronary capillaries constricted during ischaemia and reperfusion due to contraction of pericytes, significantly increasing capillary obstruction in the affected heart region.

The proportion of blocked capillaries increased from 11.6 ± 1.5% in control hearts to 73.9 ± 9.0% after ischaemia and reperfusion (P = 0.0001). This was accompanied by an approximately 40% reduction in coronary blood volume in the affected ventricular region (P = 2.2 × 10⁻⁷).

Remote ischaemic preconditioning reduced this effect. Capillary obstruction fell to 30.7 ± 5.0% in hearts receiving preconditioning compared with ischaemia alone (P = 0.0016), while myocardial perfusion returned to levels similar to those observed in control animals.

GLP-1 signalling and cardioprotection

Further experiments indicated that GLP-1 signalling was responsible for this protective response. Blocking GLP-1 receptors prevented the reduction in capillary obstruction and eliminated the restoration of coronary perfusion.

At the cellular level, activation of GLP-1 receptors relaxed pericytes and widened capillaries by activating KATP channels.

In laboratory experiments, oxygen-glucose deprivation caused capillary constriction of 15.9 ± 1.7% after 25 minutes (P = 0.0002), increasing to 23.0 ± 2.6% with longer deprivation. Treatment with a GLP-1 receptor agonist reversed this constriction and restored capillary diameter to near baseline levels (P = 6.1 × 10⁻⁶).

Blocking KATP channels pharmacologically, or removing them genetically, prevented this effect, confirming their role in GLP-1-mediated pericyte relaxation.

Limitations and potential clinical implications for GLP-1s

The study identified a potential brain-gut-heart signalling pathway that mediates cardioprotection. Nerve signals triggered by remote ischaemic preconditioning stimulate the gut to release GLP-1, thereby activating receptors on coronary pericytes, which relax capillaries and improve microvascular blood flow after ischaemia.

However, as animal models and isolated tissue experiments were mainly used, the authors cautioned that further research is needed to establish whether the same mechanism occurs in humans.

Nevertheless, commenting on the work, Professor David Attwell, Jodrell professor of physiology at UCL and study co-lead, said: ‘With an increasing number of similar GLP-1 drugs now being used in clinical practice, for conditions ranging from type 2 diabetes and obesity to kidney disease, our findings highlight the potential for these existing drugs to be repurposed to treat the risk of “no-reflow” in [myocardial infarction] patients, offering a potentially life-saving solution.’

Reference Mastitskaya S et al. GLP-1 activates KATP channels in coronary pericytes as the effector of brain-gut-heart signaling mediating cardioprotection. Nat Commun 2026;Feb 14: doi: 10.1038/s41467-026-69555-1.

This article was originally published by our sister publication Hospital Pharmacy Europe.