Exploring the role of the unique N‐termini of PDE4D variants in regulating mural cell morphology, migration and cAMP signaling (1065.1)

Abstract

Mural cells act adaptively to regulate vascular tone. After vascular damage, adoption of a synthetic phenotype increases proliferative and migratory capacity and aids in repair. Exaggerated, maladaptive responses can promote intimal hyperplasia, atherosclerotic lesion progression and arterial (re)stenosis. cAMP acting on protein kinase A (PKA) or exchange protein activated by cAMP (EPAC) regulate mural cell migration and adhesion. A cAMP signalosome in the leading edge of migrating mural cells contains PKA and phosphodiesterase (PDE) 4D8 and regulates actin assembly and migration. PDE4D isoforms share a common catalytic domain and C‐terminus. PDE4 inhibitors are non‐selective with respect to the individual PDE4 variants and compete with cAMP binding at the active site. The unique N‐termini of PDE4D isoforms are hypothesized to mediate selective protein‐protein based tethering to distinct subcellular domains. We examined the subcellular targeting, function and binding partners of the unique N‐termini of mural PDE4D variants and their impact on cAMP signalling. We show that these N‐terminal regions are important in regulating mural cell morphology, migration and adhesion.Grant Funding Source: Supported by Canadian Institutes of Health Research