Vascular smooth muscle (VSM) cyclic guanosine 3',5'-moriophosphate (cGMP) serves as a criticalregulator of many cellular functions that contribute to vessel growth after injury. Nitric oxide (NO) andcarbon 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 relevantroutes for cGMP control. Provocative new findings challenge the traditional notion that cGMP exertsvascular protection through cGMP-dependent protein kinase type (cGKI) and suggest that cGMP mayoperate via cAMP/cAK to promote vascular protection. Current studies in our laboratory focus on novel NOindependentapproaches for cGMP control as significant basic science tools and as potential cardiovasculartherapeutics. Preliminary data support a role for vascular growth control by NO-independent cGMP andsuggest mechanistic involvement of matrix metalloproteinase (MMP)-2 and MMP-9. The long-term objectiveof this research project is to investigate strategies for cGMP control of VSM growth, and the centralhypothesis of this proposal is that NO-independent cGMP protects against vascular growth and that thisoccurs 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 inattenuating 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 underliecGMP-mediated growth control in rat and mouse primary VSM cells.Pharmacology, RNA interference, and viral gene delivery approaches will be used, and conditional VSMspecificcGKI-deficient models will allow direct comparison of cGKI versus cAK mechanisms. Results areanticipated to provide insight into and further evidence for NO-independent cGMP control of the injurygrowth 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 healthconcerns, and statistics show they are still the major cause of death in American populations. We believethat results from these studies will shed light on some novel and promising strategies that could be used tominimize the severity of blood vessel injury and disease and may offer beneficial prospects for further studyin basic science research and human-based clinical studies.
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