Physiologic and pathophysiologic role of C-type natriuretic peptide

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1.Generation and Analysis of CNP-knockout and CNP-transgenic mice :To investigate the physiological significance of CNP in vivo, we generated mice with targeted disruption of CNP (CNP^<-1-> mice). The CNP^<-1-> mice show severe dwarfism as a result of impaired endochondral ossification. They are all viable perinatally, but less than half can survive during postnatal development. The skeletal phenotypes are histologically similar to those seen in patients with achondroplasia, the most common genetic form of human dwarfism. Targeted expression of CNP in the growth plate chondrocytes can rescue the skeletal defect of CNP^<-1-> mice and allow their prolonged survival. This study demonstrates that CNP acts locally as a positive regulator of endochondral ossification in vivo and suggests its pathophysiological and therapeutic implication in some forms of skeletal dysplasia.2.Genetic cross between BNP-transgenic and GC-A knockout mice :BNP, a hormone produced primarily by the cardiac ventricl … More e, is thought to be involved in a variety of homeostatic processes through its cognate receptor, guanylyl cyclase A (GC-A). To address whether BNP exerts its biological effects solely through GC-A, we produced BNP-transgenic mice lacking GC-A (BNP-Tg/GC-A^<-1-> mice) and examined their cardiovascular and skeletal phenotypes. The GC-A^<-1-> mice are hypertensive with cardiac hypertrophy relative to wild-type littermates, which is not alleviated by overexpression of BNP in BNP-Tg/GC-A^<-1-> mice. The BNP-Tg/GC-A^<-1-> mice, however, continue to exhibit marked longitudinal growth of vertebrae and long bones comparably to BNP-Tg mice. This study provides genetic evidence that BNP reduces blood pressure and cardiac weight through GC-A, whereas it dramatically alters endochondral ossification in the absence of this receptor. Therefore, the BNP-Tg/GC-A^<-1-> mice provide the first experimental model demonstrating that this natriuretic peptide can signal in a tissue-specific manner through a receptor other than GC-A. Less