Heterogeneous distribution of endothelial phosphodiesterases in mesenteric arteries from mice

Nitric oxide (NO) is a major endothelium‐derived signalling pathway regulating vascular tone through stimulation of cGMP production in smooth muscle cells (SMCs). Control of cGMP levels is thus essential to vascular function. Phosphodiesterases (PDEs) are key regulators of intracellular cGMP and cAMP levels. PDE1, PDE5, PDE6 and PDE9 preferentially degrade cGMP over cAMP. Although endothelium is the main source of NO, little is known on cGMP levels and their regulation by PDEs. Characterization of endothelial PDEs has therefore been undertaken in mesenteric arteries (MA). mRNA encoding for PDE1, PDE5 & PDE9 was found in mesenteric arteries. Interestingly, expression of both subunits (α & β) of PDE6, a retina‐specific PDE, was detected in MA. PDE5 and PDE9 appear to be homogeneously distributed in both endothelial cells (ECs) and SMCs as evidenced by immunohistochemistry. Although PDE6 was not detected in SMCs, both PDE6 subunits were found in ECs from MA. Moreover, PDE6α and β are localized to the perinuclear region exclusively. These data suggest that cGMP microdomains are presents in native endothelium. A mathematical model based on PDEs properties and intracellular localization is used to estimate local cGMP levels in ECs. This is the first evidence of potential cGMP microdomains in ECs and suggests a role for localized regulation of cGMP for endothelial function. Supported by FICM, CFI and FRSQ