Phosphodiesterase Inhibition Decreases Vascular Endothelial Permeability Without Global Changes in cAMP: Potential Role of Phosphodiesterase/VE‐Cadherin Signaling Complexes

Vascular endothelial cells (VECs) play an essential role in regulating the passage of macromolecules and cells between the blood stream and underlying tissues. The second messenger 3′,5′ cyclic adenosine monophosphate (cAMP) regulates numerous events in VECs, including permeability. Since human VECs express several distinct cAMP‐hydrolyzing phosphodiesterases (PDEs), in these studies we investigated if selective pharmacological inhibition of these PDEs could influence VEC permeability. Interestingly, we found that while inhibitors of PDE2, PDE3 or PDE4 family enzymes did not increase total VEC cAMP levels in either human aortic or human microvascular VECs, these agents did decrease permeability in each of these cell types. Consistent with the idea that the PDE inhibitors may activate cAMP‐effectors to bring about these effects, selective activation of either protein kinase A (PKA) or exchange proteins activated by cAMP (EPACs), also decreased VEC permeability. This data is consistent with the idea that PDE inhibition causes small increases in localized “pools” of cAMP, and in the context of these studies, an increase in cAMP in the membrane sub‐domains that control permeability. In our laboratory we have shown that certain PDEs interact with VE‐cadherin‐containing cellular complexes, in some instances with PKA and/or EPACs.