Tissue-specific regulation of NO-GC isoforms in the cardiovascular system

Due to its involvement in the regulation of smooth muscle relaxation, platelet aggregation, and endothelial homeostasis, the nitric oxide (NO) / cyclic guanosine monophosphate (cGMP) cascade plays an important role in cardiovascular health and disease. Cyclic GMP is formed by NO-sensitive guanylyl cyclases (NO-GCs) in response to stimulation by NO. It is also thought that cGMP signaling is influenced by other signaling cascades and hormonal mediators. Interestingly, there is evidence that these interactions are altered by various diseases. In addition, the NO/cGMP signaling pathway is modified by the regulation of effector molecules at the transcriptional and post-transcriptional level, as well as by cellular communication via gap junctions or multidrug resistance-associated proteins. In this context, the use of mouse models and state-of-the-art technologies (e.g., gene targeting or fluorescent indicators) has provided valuable insights into the molecular physiology of cGMP-related signaling processes. Stimulators of NO-GCs and inhibitors of cGMP-degrading enzymes have also found their way into the treatment of chronic heart failure, erectile dysfunction, coronary heart disease, and pulmonary hypertension. Nevertheless, it is still elusive whether cGMP is exclusively beneficial in cardiovascular diseases at the cellular and molecular level. Therefore, a better understanding of cGMP signaling pathways is important for the development of appropriate new therapeutic strategies based on the modification of cGMP levels in the heart and blood vessels. This review article therefore aims to provide an overview of the most important findings of cGMP research in the cardiovascular system and to summarize the known interactions of the system with other relevant cardiovascular mediators in health and disease.