Age-dependent remodelling of arterial chemoafferent innervation in hypertension

AIMS: Elevated sympathetic nerve activity (eSNA) is a hallmark of cardiovascular disease and represents an important clinical target for disease management. A known driver of eSNA is aberrant signalling from, and sensitization of, the carotid body (CB) arterial chemoreceptors. Sensitization is coupled with CB hypertrophy, the cause of which remains unclear. Here, we set out to characterize the morphological basis of CB hypertrophy in hypertension to understand its aberrant activity. METHODS AND RESULTS: Using high-throughput fluorescence microscopy, we mapped the neurovascular interface and chemoafferent innervation of the CB of spontaneously hypertensive rats (SHR) across multiple age groups. We show that CB hypertrophy driven by chemosensory (type I) cell hyperplasia and an expanded vascular network is evident in 4-6-week-old SHR without established hypertension. Specifically, CB hypertrophy in the SHR is linked to increased chemoafferent innervation and an age-dependent remodelling of nerve fibre composition. CONCLUSIONS: CB hypertrophy in hypertension is associated with chemosensory hyperplasia and angiogenesis, likely mediated by impaired HIF-PHD signalling in the SHR. We propose that CB size may serve as a candidate marker of chemoafferent sensitivity and the efficacy of therapies targeting the CB. However, further validation in humans is needed to support this link. Neurotrophic pathways promoting increased chemoafferent innervation in hypertension are proposed as a potential target for modulating CB activity in sympathetically mediated diseases.