A Paraventricular Nucleus–Rostral Ventrolateral Medulla Pathway Contributes to Myocardial Ischemia/Reperfusion Injury

Abstract Myocardial ischemia/reperfusion injury (MIRI), the major pathophysiology of cardiovascular disease, is a crucial therapeutic focus. To date, whether MIRI is centrally mediated and its underlying processing hierarchy remain elusive. We show that the electrical activity of the paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) neurons increased after MIRI in a mouse model. We identified a neural circuit involving glutamatergic projections from the paraventricular nucleus (Glu PVN ) to tyrosine hydroxylase–expressing neurons in the rostral ventrolateral medulla (TH RVLM ) that contributes to MIRI. Transneuronal tracing with neurotropic viruses indicated that the TH RVLM neurons project directly to the spinal preganglionic neurons and then to the stellate ganglion, two critical neural nodes along the brain–heart axis. Chemogenetic inhibition of the Glu PVN →TH RVLM circuit or cervical sympathetic blockade reduced the level of norepinephrine in the heart and thereby prevented MIRI. Furthermore, pharmacological blockade of myocardium β-receptors also reduced MIRI. This brain–heart circuit that promotes MIRI represents a potential therapeutic target for MIRI treatment.