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

A cardiac neurovascular unit (NVU) exists in which sympathetic fibers frequently lie in close anatomical apposition to capillary endothelial cells in both mouse and human hearts.

• Identified using confocal and ultrastructural imaging in mouse and human hearts
• A substantial fraction of tyrosine hydroxylase-positive processes aligns with the capillary network
• This structural relationship suggests a framework for local neurovascular communication
• The NVU integrates sympathetic, endothelial, and myocyte compartments

Cardiac aging was associated with fragmentation and rarefaction of sympathetic fibers accompanied by cardiomyocyte atrophy and capillary remodeling.

• Capillary remodeling in aging was characterized by increased vessel density and reduced caliber
• Sympathetic fiber changes in aging included fragmentation and rarefaction of tyrosine hydroxylase-positive processes
• Cardiomyocyte atrophy was observed concurrent with sympathetic and vascular changes
• Findings were demonstrated using confocal imaging in mouse hearts

Pharmacological sympathectomy with 6-hydroxydopamine (6-OHDA) in young mice reproduced the aging-associated changes in capillary morphology and cardiomyocyte trophism.

• 6-OHDA treatment in young mice recapitulated capillary remodeling (increased vessel density and reduced caliber) seen in aging
• Cardiomyocyte atrophy was also reproduced by pharmacological sympathectomy
• This established a causal link between sympathetic integrity, cardiomyocyte trophism, and microvascular organization
• Control experiments excluded direct vascular toxicity of 6-hydroxydopamine as an alternative explanation

Combined adrenalectomy and sympathectomy confirmed that the microvascular and cardiomyocyte effects of sympathetic denervation were independent of circulating catecholamines.

• Adrenalectomy was performed alongside sympathectomy to eliminate circulating catecholamine contribution
• The capillary remodeling and cardiomyocyte atrophy phenotype persisted after combined adrenalectomy-sympathectomy
• This confirmed the effects were due to local sympathetic innervation rather than systemic catecholamine levels

Transplanted human hearts showed an early-established and persistent reduction in capillary diameter compared with controls, mirroring the phenotype observed in sympathectomized and aged mice.

• Heart transplantation was used as an established clinical model of abrupt cardiac denervation
• Reduced capillary caliber was observed in transplanted human hearts relative to non-transplanted controls
• The reduction in capillary diameter was described as early-established and persistent
• This finding mirrored the capillary remodeling phenotype observed in aged and pharmacologically sympathectomized mice