*2.4. Role of CgA Fragment/Neuropilin-1 Interactions in Cardiovascular Regulation*

Global neuropilin-1 null mice develop severe cardiovascular abnormalities, indicating that neuropilin-1 has also a crucial cardiovascular function [60]. In addition, the observation that the selective knockout of neuropilin-1 in cardiomyocytes and vascular smooth muscle cells leads to cardiomyopathy, increased propensity to heart failure, and reduced survival after myocardial infarction, suggests a role for neuropilin-1 in the pathogenesis of cardiovascular diseases [61]. Based on these notions, and on the fact that CgA is the precursor of various cardio-regulatory fragments, a recent study has investigated the possibility that the fragment CgA1-373 affects the myocardial performance by interacting with neuropilin-1 [46]. Hemodynamic assessment (performed using the Langendorff rat heart model) and studies on the mechanism of action (performed using perfused hearts and cultured cardiomyocytes) have shown that CgA1-373 can elicit negative inotropism and vasodilation, whereas no significant effects were observed with CgA1-372, which lacks the C-terminal arginine necessary for neuropilin-1 recognition [46]. These effects were abolished by antibodies directed against the PGPQLR373 sequence of CgA1-373. Furthermore, ex vivo and in vitro studies showed that these biological effects are mediated by the endothelium and involve neuropilin-1, Akt/NO/Erk1,2 activation and S-nitrosylation [46]. The effects elicited by CgA1-373 and the lack of activity observed with CgA1-372 suggest that CgA1-373 is a cardioregulatory factor and that the removal of its C-terminal arginine by carboxypeptidases may work as an important switch for "*turning off* " its cardio-regulatory activity.
