Cyclic Nucleotide Phosphodiesterases in the Cardiovascular System

 

The Maurice lab investigates the role that subcellular compartment-specific hydrolysis of cyclic nucleotide (cAMP and cGMP), by the cyclic nucleotide phosphodiesterases (PDEs), plays in promoting selective cyclic nucleotide-signaling in human arterial endothelial and smooth muscle cells. Since virtually all functions of these cell types are regulated by cyclic nculeotide-signaling systems, our studies may allow identification of novel therapeutic targets for managenment of multiple cardiovascular diseases, including atherosclerosis and restenosis, and in important vascular processes such as vasculogenesis and angiogenesis.


In cells of the cardiovascular system, cAMP- and cGMP-signaling systems each regulate multiple cellular functions including celularl adhesion, migration and proliferation. While adhesion, migration and proliferation of are adaptive functions in both vascular endothelial and smooth muscle cells, their dysregulation can induce or promote cardiovascular diseases such as heart failure, hypertension, stroke and atherosclerosis.

Using a multidisciplinary approach, and utilizing a wide variety of techniques corresponding to pharmacology, molecular biology, cell biology, and biochemistry, the Maurice Lab focuses on the molecular basis of cyclic nucleotide-mediated effects in vascular tissues. While our studies integrate effects mediated by the enzymes that synthesise cAMP and cGMP (adenylyl cyclase and guanylyl cyclase), the effector proteins that propagate cell signals (Protein Kinase A, Protein Kinase G and the exchange protein activated by cAMP (EPAC)), our main focus is on the enzymes that hydrolyze and thus inactivate these two second messengers, Cyclic Nucleotide Phosphodiesterases (PDEs). Specifically, our studies have focused on enzymes of the PDE1, PDE2, PDE3, PDE4 and PDE5 families and their role in platelets, arterial endothelial and vascular smooth muscle cells. 

We strive to investigate how the PDEs regulate multiple cell functions and have identified multiple signaling complexes that pair both cAMP/cGMP effector proteins (PKA, PKG, EPAC) alongside PDEs forming functional units in cells that efficiently monitor cyclic nucleotide signaling. Utilization of fluorescent microscopy and live cell imaging allow us to examine these complexes in their specific subcellular location and how they dynamically regulate increases in cAMP or cGMP. Our research has helped in confirming that intracellular signaling occurs in a spatial and temporal manner and that subcellular localization of signaling enzymes contributes to signal specificity. When combined, these approaches allow us to study nucleotide-mediated signalling both at a molecular as well as a cellular level and identify potential targets for future therapeutic development.