Vascular smooth muscle (VSM) cyclic guanosine 3',5'-moriophosphate (cGMP) serves as a critical regulator of many cellular functions that contribute to vessel growth after injury. Nitric oxide (NO) and carbon monoxide (CO) operate as soluble guanylate cyclase (sGC)-activating ligands for cGMP synthesis; however, limitations of NO and CO signaling warrant study into alternate, pathophysiologically relevant routes for cGMP control. Provocative new findings challenge the traditional notion that cGMP exerts vascular protection through cGMP-dependent protein kinase type (cGKI) and suggest that cGMP may operate via cAMP/cAK to promote vascular protection. Current studies in our laboratory focus on novel NOindependent approaches for cGMP control as significant basic science tools and as potential cardiovascular therapeutics. Preliminary data support a role for vascular growth control by NO-independent cGMP and suggest mechanistic involvement of matrix metalloproteinase (MMP)-2 and MMP-9. The long-term objective of this research project is to investigate strategies for cGMP control of VSM growth, and the central hypothesis of this proposal is that NO-independent cGMP protects against vascular growth and that this occurs through cAK signals. Two Specific Aims will be used to test this hypothesis: Aim 1 will analyze the roles of NO-independent cGMP and cGMP-directed cGKI/cAK signaling in attenuating vascular remodeling in the rat balloon injury and mouse wire denudation injury models. Aim 2 will examine matrix-based mechanisms including cell migration and MMP balance that underlie cGMP-mediated growth control in rat and mouse primary VSM cells. Pharmacology, RNA interference, and viral gene delivery approaches will be used, and conditional VSMspecific cGKI-deficient models will allow direct comparison of cGKI versus cAK mechanisms. Results are anticipated to provide insight into and further evidence for NO-independent cGMP control of the injury growth response in VSM and shed light upon cGMP-directed MMPs in mediating these events. Injuries and diseases of the heart and blood vessels are wide-ranging and very serious public health concerns, and statistics show they are still the major cause of death in American populations. We believe that results from these studies will shed light on some novel and promising strategies that could be used to minimize the severity of blood vessel injury and disease and may offer beneficial prospects for further study in basic science research and human-based clinical studies.