Cardiovascular disease (CVD) remains the leading causes of morbidity and mortality in the developed world. The major forms of CVD include coronary heart disease (angina， myocardial infarction)， cerebrovascular disease (stroke)， and hypertension. Pathological vascular remodeling， such as atherosclerosis， is the main trigger of myocardial infarction and stroke. A normal artery consists of three main layers: the intima， media， and adventitia. The intima is a single layer of endothelial cell lining the lumen of the blood vessel. The medial layer is comprised of several layers of vascular smooth muscle cells (VSMCs) with each layer being interposed by extracellular matrix proteins. The adventitial layer mainly includes elastic tissue， such as collagen， and some fibroblasts.  Under normal conditions， VSMCs residing in the media of vessels are quiescent with a very low turnover rate. Quiescent VSMCs are highly differentiated cells that possess the “contractile” phenotype and function principally to maintain vascular tone. In response to biological and mechanical injury， VSMCs exhibit phenotypic plasticity and undergo phenotypic modulation， changing from quiescent/contractile phenotype to an active/synthetic one.  Synthetic VSMCs contribute to neointima formation by downregulating contractile proteins and acquiring the capacity to proliferate， migrate， and produce extracellular matrix proteins. Therefore， phenotypic modulation of VSMCs plays a key role in the pathogenesis of cardiovascular disorders such as atherosclerosis， postangioplasty restenosis， bypass vain graft failure， and cardiac allograft vasculopathy. The endothelium plays a critical role in controlling VSMCs response. Healthy endothelium synthesizes and secretes factors that relax VSMCs and inhibit VSMC phenotypic modulation. For example， prostacyclin (PGI2) and nitric oxide (NO)， two major factors released from endothelium， stimulate production of cAMP and cGMP， respectively， in underlying VSMCs.  cAMP and cGMP have a variety of  biological effects in VSMCs， such as promoting VSMC relaxation， inhibiting VSMC proliferation， migration， and extracellular matrix synthesis. Cyclic nucleotide phosphodiesterases (PDEs)， by catalyzing the hydrolysis of cAMP and cGMP， regulate the amplitude， duration， and compartmentalization of intracellular cyclic nucleotide signaling. PDEs constitute a large superfamily of enzymes. To date more than 50 different isoforms have been identified and grouped into 11 broad families based on their distinct kinetic properties， regulatory mechanisms， and sensitivity to selective inhibitors. More importantly， PDEs appear to be promising pharmacological targets for therapeutic agents due to the presence of multiple structurally different， tissue-specific， differentially regulated， and functionally distinct isoforms. Several drugs， such as Viagra， have been shown to have unique specific effects via selectively inhibiting individual PDE isozymes.

    My lab is particularly interested in PDE1 isozymes due to their unique role in regulating Ca2+/calmodulin stimulated cyclic nucleotide hydrolysis. We found that angiotensin II (Ang II)， via increasing intracellular Ca2+ concentrations， rapidly activates PDE1 in VSMC. Ang II-mediated activation of PDE1 contributes to the effects of Ang II on attenuation of cGMP accumulation stimulated by NO. These suggest that PDE1 plays an important role in the crosstalk between Ca2+ and cGMP signaling， and unveils a novel mechanism by which Ang II antagonizes the effect of NO via stimulation of PDE1 activation and attenuation of cGMP accumulation. Imbalance between Ang II and NO has been implicated in the pathophysiology of a variety of cardiovascular diseases. Therefore， alteration in PDE1 function may lead to pathological consequences. For example， PDE1A is a Ca2+/calmodulain-stimualted PDE that preferentially hydrolyzes cGMP in VSMCs. We found that the activity and expression of PDE1A was selectively induced in nitrate-tolerant vessels， which may represent one important mechanism by which NO/cGMP-mediated vasodilation is desensitized and vasoconstrictor/Ca2+-mediated vasoconstriction is supersensitized in the nitrate tolerant model. Recently， we also found that PDE1A is predominantly localized in the cytoplasm of “contractile” VSMCs found in the medial layer of arteries， but is mainly localized in the nucleus of “synthetic” VSMCs found in neointima， atherosclerotic lesions， and subcultured VSMCs. We further demonstrated that nuclear PDE1A controls the growth and survival of “synthetic” VSMCs， whereas cytoplasmic PDE1A may regulate the contractility of “contractile” VSMCs. To determine the role of PDE1 in vascular remodeling in vivo， we examined the effects of PDE1 inhibition on vascular remodeling after the injury.  We found that in a mouse model of carotid artery injured by complete cessation of blood flow via carotid artery ligation， perivascularly administered PDE1 inhibitor significantly attenuated neointima formation.  In addition， we also found that PDE inhibition dose-dependently reduced human saphenous vein remodeling in an ex vivo culture model.  Further study of mechanism demonstrated that PDE1A regulates beta-catenin/TCF signaling in “synthetic” VSMCs. Inhibition of PDE1A specifically upregulated phosphatase PP2A B56 gamma subunit gene expression， thereby attenuating nuclear GSK3beta/beta-catenin signaling by promoting beta-catenin degradation. In addition to VSMCs， nuclear PDE1A is also upregulated in adventitial myofibroblasts that contribute to neointima formation and vascular remodeling.  Taken together， these data strongly suggest that PDE1， particular PDE1A， plays a critical role in cardiovascular diseases associated with VSMC proliferation such as atherosclerosis and restenosis. These studies may not only bring novel insights into our understanding of the complex regulatory mechanisms underlying the pathogenesis of cardiovascular diseases but may also lead to the development of novel therapeutic strategies.