The second messenger cGMP mediates many useful, but also unwanted effects of the endogenous signalling molecules such as NO, CO and natriuretic peptides. A better understanding of the signal transduction pathways initiated by cGMP could generate new therapeutic strategies. cGMP signals through cGMP-dependent protein kinases (cGK), phosphodiesterases, and eventually cAMP kinase. cGKs are encoded by two genes, cgkI and cgkII. Effects of cGMP in the cardiovascular system are mainly mediated by cGKI. Alternative splicing of the amino-terminus generates two isozymes, the cGKIaand cGKIbthat are expressed individually or together in a wide variety of cells. Deletion of exon 10 in the cgkI gene inactivates both isozymes and resulted in a multiple morbid animal including changes in blood pressure, vascular remodeling, learning and memory, and altered recruiting of granulocytes to inflammatory sites. These animals are difficult to analyze, be­cause they die during the first 6 weeks. So far, we were unable to investigate the cardio-vascular significance of the two isozymes cGKIaand cGKIb. We have now established two mouse lines that express the Iaor the Ibisozyme specifically in all smooth muscle cells. Remarkably, both mouse lines live up to a year without showing an overt pheno­type. These mouse lines will allow analyzing the cardiovascular function of cGMP and the cGKI isozymes in adult “healthy” animals.