The cardiac neurovascular unit: sympathetic control of the capillary network in aging and transplantation

Sympathetic nerves are key regulators of cardiac performance, yet their micro-anatomical relationship with the coronary microcirculation remains incompletely defined. Here, we identify a previously underappreciated cardiac NeuroVascular Unit (NVU), in which sympathetic fibers frequently lie in close anatomical apposition to capillary endothelial cells. Using confocal and ultrastructural imaging in mouse and human hearts, we demonstrate that a substantial fraction of tyrosine hydroxylase-positive processes aligns with the capillary network, suggesting a structural framework for local neurovascular communication. Cardiac aging was associated with fragmentation and rarefaction of sympathetic fibers, accompanied by cardiomyocyte atrophy and capillary remodeling characterized by increased vessel density and reduced caliber. Pharmacological sympathectomy in young mice reproduced these changes, establishing a causal link between sympathetic integrity, cardiomyocyte trophism, and microvascular organization. Control experiments excluded direct vascular toxicity of 6-hydroxydopamine, and combined adrenalectomy-sympathectomy confirmed that these effects were independent of circulating catecholamines. Analysis of transplanted human hearts, an established clinical model of abrupt cardiac denervation, revealed an early-established and persistent reduction in capillary diameter compared with controls, mirroring the phenotype observed in mice. Together, these findings define the cardiac NVU as a structural neurovascular interface integrating sympathetic, endothelial, and myocyte compartments, with potential functional implications. Recognition of this neurovascular architecture revises current paradigms of cardiac autonomic regulation and suggests new avenues for targeting microvascular-neuronal apposition in cardiac aging and transplantation.<b>NEW & NOTEWORTHY</b> This study identifies a previously unrecognized cardiac neurovascular unit in which sympathetic fibers lie in close anatomical apposition to capillary endothelial cells. Disruption of this cell-to-cell interface, during aging, pharmacological sympathectomy, or following heart transplantation, is associated with capillary remodeling and cardiomyocyte atrophy. These findings broaden current concepts of cardiac autonomic regulation and highlight the coronary microcirculation as a structural component shaped by sympathetic integrity.