The Role of the Axonal Guidance Cue Semaphorin 3A in Innervation of the Postnatal Heart in Health and Disease

During cardiac development, the heart is innervated by the autonomous nervous system. After development, neurons of the autonomic nervous system have limited capacity for growth and regeneration. However, in recent decades, it has become clear that cardiac nerves can regenerate after cardiac damage. Excessive reinnervation, so-called sympathetic hyperinnervation, may render patients vulnerable to ventricular arrhythmias and heart failure. Several studies have investigated axonal guidance cues as mediators of cardiac innervation. Axonal guidance cues direct neuronal growth of the axon and play a significant role in the regeneration and remodelling of cardiac autonomic innervation after cardiac damage. This review focusses on the current literature regarding the axonal guidance cue group of semaphorins and their function in the healthy and diseased postnatal heart. In view of cardiac innervation, most studies have focussed on semaphorin 3A (SEMA3A), whereas less is known about the function of the other semaphorin classes. SEMA3A is a neuronal repellent and is associated with a decrease in the density of sympathetic neurons in the heart. Its decline in expression after myocardial infarction plays a role in the development of sympathetic hyperinnervation and the subsequent increased risk of ventricular arrhythmias. In congestive heart failure, the opposite occurs: an increase in SEMA3A expression underlies decreased nerve density that may also serve as a substrate for ventricular arrhythmias. Although the literature on their role in cardiac innervation is still relatively scarce, semaphorins, especially SEMA3A, seem worthwhile to consider when exploring options to modulate pathologic innervation patterns in cardiovascular disease.