Anatomical congruence of peripheral nerves and blood vessels is well recognized in the developing heart. Large-diameter coronary veins mediate the projection of cardiac sympathetic axons in the sub-epicardial layer of the dorsal ventricular wall of the developing heart. This association enables subsequent innervation of final target cells such as coronary arteries and myocardial cells in the deeper myocardial layer. In vitro, coronary smooth muscle cells direct extension of sympathetic axons. These data suggest that large-diameter coronary veins serve as an intermediate template for distal sympathetic axon extension. This proposed mechanism underlies a unique, stereotypical pattern of innervation that is adapted to the complex tissue structure and physiology of the heart (manuscript in submission). Our results suggest that sympathetic innervation of the heart is not random. Rather, there appears to be a coordinated process, which ensures the proper distribution of sympathetic axons in the sub-epicardial layer, ultimately allowing topological targeting of axons to specific regions in the deeper myocardial layer. We provide here the first evidence that coronary veins serve as intermediate conduits for distal sympathetic axon extension. Our results suggest that target organs of sympathetic ganglia may possess unique and stereotypical patterns of innervation, mediated by tissue sub-structures, such as coronary veins in the heart, that are adapted to complex tissue structure and physiology.
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