Nardilysin controls cardiac sympathetic innervation patterning through regulation of p75 neurotrophin receptor.

Cardiac sympathetic innervation is critically involved in the regulation of circulatory dynamics. However, the molecular mechanism for the innervation patterning has remained elusive. Here, we demonstrate that nardilysin (NRDC,Nrdc), an enhancer of ectodomain shedding, regulates cardiac sympathetic innervation. Nardilysin-deficient (Nrdc(-/-)) mice show hypoplastic hearts, hypotension, bradycardia, and abnormal sympathetic innervation patterning. While the innervation of left ventricle (LV) of wild-type mice is denser in the subepicardium than in the subendocardium,Nrdc(-/-)LV lacks such a polarity and is uniformly and more abundantly innervated. At the molecular level, the full-length form of p75 neurotrophin receptor (p75(NTR),Ngfr) is increased inNrdc(-/-)LV due to the reduced ectodomain shedding of p75(NTR). Importantly, the reduction of p75(NTR)rescued the abnormal innervation phenotype ofNrdc(-/-)mice. Moreover, sympathetic neuron-specific, but not cardiomyocyte-specific deletion ofNrdcrecapitulated the abnormal innervation patterning ofNrdc(-/-)mice. In conclusion, neuronal nardilysin critically regulates cardiac sympathetic innervation and circulatory dynamics via modulation of p75(NTR).