Introduction
Smooth muscle cells (SMCs) in the arterial wall are normally found in a contractile,
nonproliferative state. These SMCs are continuously exposed to agents that elevate
cyclic AMP (cAMP) and cyclic GMP (cGMP), such as prostacyclin and nitric oxide (NO)
released from the endothelium. Both cAMP and cGMP potently inhibit SMC proliferation
by antagonizing major signaling pathways induced by growth factors, such as platelet-derived
growth factor. Different forms of injury to the endothelium result in proliferation
of the SMCs and can develop into atherosclerosis, restenosis, or arterial thickening
associated with neonatal pulmonary hypertension. In human adult aorta, cAMP and cGMP
levels are tightly regulated by synthesis and degradation. The latter is mediated
by at least two different cAMP phosphodiesterases (PDEs), PDE3 and PDE4, and three
different PDEs that degrade mainly cGMP, PDE1A, PDE1B, and PDE5. Strikingly, expression
of a new PDE that degrades both cAMP and cGMP, PDE1C, is markedly induced in proliferating
SMCs from the same aorta in culture, whereas its expression is nondetectable in contractile
aorta. We propose that, for a human arterial SMC to be able to efficiently proliferate,
and perhaps even to undergo a phenotypic change from a quiescent to a proliferative
phenotype, it has to efficiently degrade inhibitory cAMP and cGMP. In human SMCs,
PDE1C is induced to degrade these cyclic nucleotides. Understanding the role of PDE1C
in SMC proliferation may provide the basic information necessary for development of
highly specific PDE1C inhibitors that target proliferating SMCs in cardiovascular
disease.
