Selective Tethering Of Mural Cell Phosphodiesterase 4d Variants Allows Spatial Resolution Of Camp-Mediated Events Required For Adhesion And Migration

Mural cells can inhibit vascular lesion progression and stabilize angiogenic vascular tubes during tissue repair or they can act maladaptively and promote atherosclerotic lesion progression and arterial stenosis; effects dependent on binding to selected extracellular matrix (ECM) proteins and on choosing between chemotactic gradients. Although cAMP, acting via protein kinase A (PKA) or exchange protein activated by cAMP (EPAC), impacts mural cell adhesion or migration, a consensus has emerged that individual actions occur within discrete “compartments” populated by cAMP‐signaling complexes (cAMP‐signalosomes). Previously we showed that PKA in leading edge structures in migrating mural cells was in a cAMP‐signalosome also populated by one (PDE4D8) of the five PDE4D variants in these cells. Displacing PDE4D8 from these structures activated PKA, inhibited actin assembly and inhibited migration. Here we report on the subcellular targeting of the five mural cell PDE4D variant, identify their interacting protein partner(s), and assess their impact on mural cell adhesion/migration. Our data show that each PDE4D variant impacts mural cell cAMP‐signaling and selectively control specific cellular functions.