cAMP and cGMP control crucial signaling mechanisms that regulate growth and development of the cardiovascular system (Rybalkin et al. Circ Res, 2003). For example, during formation of advanced atherosclerotic lesions and restenosis after angioplasty vascular smooth muscle cells of blood vessels undergo transformation from the contractile to proliferative phenotype and cyclic nucleotides are able to inhibit proliferation of these cells. We recently showed that calcium, calmodulin-stimulated cyclic nucleotide phosphodiesterase 1C (PDE1C) is induced in proliferating human SMCs ex vivo and in vivo, and that inhibition of PDE1C results in an inhibition of human arterial smooth muscle cell proliferation (Rybalkin et al. Circ Res 2002). Studies of the mechanisms of regulation of various PDE isozymes in different types of smooth muscle cell will lead to better understanding of SMC proliferation in human cells and reveal potential clinical use of individual PDE isoforms expressed in these cells.
Nitric oxide or other endogenous vasodilators control a variety of cardiovascular, nervous and immune systems by stimulation of cGMP synthesis. In smooth muscle increases in intracellular cGMP concentrations lead to significant changes in smooth muscle tone. cGMP specific PDE (PDE5) as a major cGMP-hydrolyzing enzyme expressed in smooth muscle cells effectively controls the development of smooth muscle relaxation, and lately it became a target for successful drug development (sildenafil - "Viagra", tadalafil - "Cialis" and vardenafil - "Levitra"). Recently we have demonstrated that cGMP binding to the GAF A domain of PDE5 is necessary and sufficient to achieve full activation of PDE5 (Rybalkin et al. EMBO J 2003). It was also suggested that PDE5 could exist in at least two different conformational states: a non-activated state with low intrinsic catalytic activity and an activated state formed upon cGMP binding to the GAF A domain. The mechanism of such conversion and the functional roles of cGMP binding sites in modification of PDE5 catalytic activity are currently under investigation.