Dynamic cAMP fluctuations that are restricted to a sub-plasma-membrane domain strengthen endothelial barrier integrity. Phosphodiesterases (PDEs) localize within this domain where they limit cAMP diffusion into the bulk cytosolic compartment; however, the molecular identity of PDEs responsible for endothelial cell membrane cAMP compartmentation remain poorly understood. Our present findings reveal that the D4 splice variant of the PDE4 phosphodiesterase family – PDE4D4 – is expressed in pulmonary microvascular endothelial cells, and is found in plasma membrane fractions. PDE4D4 interacts with αII spectrin within this membrane domain. Although constitutive PDE4D4 activity limits cAMP access to the bulk cytosol, inhibiting its activity permits cAMP to access a cytosolic domain that is rich in microtubules, where it promotes protein kinase A (PKA) phosphorylation of tau at Ser214. Such phosphorylation reorganizes microtubules and induces interendothelial cell gap formation. Thus, spectrin-anchored PDE4D4 shapes the physiological response to cAMP by directing it to barrier-enhancing effectors while limiting PKA-mediated microtubule reorganization.