Genetic models reveal that brain natriuretic peptide can signal through different tissue-specific receptor-mediated pathways

Brain natriuretic peptide (BNP), a hormone produced primarily by the cardia c ventricle, is thought to be involved in a variety of homeostatic processe s through its cognate receptor, guanylyl cyclase A (GC-A). We previously cr eated transgenic mice overexpressing BNP under the control of the liver-spe cific human serum amyloid P component promoter (BNP-transgenic mice) and de monstrated that they exhibit reduced blood pressure and cardiac weight acco mpanied by an elevation of plasma cGMP concentrations and marked skeletal o vergrowth through the activation of endochondral ossification. To address w hether BNP exerts its biological effects solely through GC-A, we produced B NP-transgenic mice lacking GC-A (BNP-Tg/GC-A(-/-) mice) and examined their cardiovascular and skeletal phenotypes. The GC-A(-/-) mice are hypertensive with cardiac hypertrophy relative to wild-type littermates, which is not a lleviated by overexpression of BNP in BNP-Tg/GC-A(-/-) mice; The BNP-Tg/GC- A(-/-) mice, however, continue to exhibit marked longitudinal growth of ver tebrae and long bones comparably to BNP-Tg mice. This study provides geneti c 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(-/-) mice provide the first expe rimental model demonstrating that this natriuretic peptide can signal in a tissue-specific manner through a receptor other than GC-A.