Characterisation of the physiological roles and pathological significance of endothelium-derived C-type natriuretic peptide: a novel vasoprotective signalling paradigm. (360G-Wellcome-084449_Z_07_Z)

We have identified C-type natriuretic peptide (CNP) as a key endothelium-derived vasorelaxant mediator in mesenteric and coronary resistance arteries, thereby assigning a pivotal role to this peptide in the regulation of local blood flow. Moreover, we have shown that CNP acts as an endogenous protective mechanism against ischaemia-reperfusion injury and regulates the activity of circulating cells and platelets. These seminal observations suggest that CNP maintains a substantial anti-atherogenic/ anti-thrombotic effect on the blood vessel wall. Consequently, loss of this cytoprotective activity may be an important contributor to cardiovascular pathogenesis and therefore represent a novel therapeutic target. This proposal will employ a multi-disciplinary approach including molecular & cell biology, biochemical studies and in vitro/in vivo pharmacology to fully elucidate the (patho)physiological cardioprotective roles of CNP. The key lines of research are: (a) Investigation of the tr anscriptional and biochemical regulation of CNP and functional consequences of this in vivo; (b) Microscopic and electrophysiological analysis of CNP-dependent signalling in vascular cells; (c) Investigation of the mechanisms underlying the anti- & pro- mitogenic properties of CNP; (d) Characterisation of the key physiological and pathological roles of CNP in the cardiovascular system using a novel conditional knockout mouse.