Differential regulation of vascular smooth muscle and endothelial cell proliferation in vitro and in vivo by cAMP/PKA-activated p85αPI3K

Daniele Torella, Cosimo Gasparri, Georgina M Ellison, Antonio Curcio, Angelo Leone, Carla Vicinanza, Valentina Galuppo, Isabella Mendicino, Walter Sacco, Iolanda Aquila, Francesca Chiara Surace, Maria Luposella, Gilda Stillo, Valter Agosti, Claudia Cosentino, Enrico V Avvedimento, Ciro Indolfi

    Research output: Contribution to journalArticlepeer-review

    34 Citations (Scopus)

    Abstract

    cAMP inhibits proliferation in most cell types, triggering different and sometimes opposing molecular pathways. p85alpha (phosphatidylinositol 3-kinase regulatory subunit) is phosphorylated by cAMP/PKA in certain cell lineages, but its effects on vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) are unknown. In the present study, we evaluated 1) the role of p85alpha in the integration of cAMP/PKA-dependent signaling on the regulation of VSMC and EC growth in vitro; and 2) the effects of PKA-modified p85alpha on neointimal hyperplasia and endothelial healing after balloon injury in vivo. Plasmid constructs carrying wild-type and PKA-modified p85alpha were employed in VSMCs and ECs in vitro and after balloon injury in rat carotid arteries in vivo. cAMP/PKA reduced VSMC proliferation through p85alpha phosphorylation. Transfected PKA-activated p85alpha binds p21ras, reducing ERK1/2 activation and VSMC proliferation in vitro. In contrast, EC proliferation inhibition by cAMP is independent from PKA modification of p85alpha and ERK1/2 inhibition; indeed, PKA-activated p85alpha did not inhibit per se ERK1/2 activation and proliferation in ECs in vitro. Interestingly, cAMP reduced both VSMC and EC apoptotic death through p85alpha phosphorylation. Accordingly, PKA-activated p85alpha triggered Akt activation, reducing both VSMC and EC apoptosis in vitro. Finally, compared with controls, vascular gene transfer of PKA-activated p85alpha significantly reduced neointimal formation after balloon injury in rats, without inhibiting endothelial regeneration of the injured arterial segment. In conclusions, PKA-activated p85alpha integrates cAMP/PKA signaling differently in VSMCs and ECs. By reducing neointimal hyperplasia without inhibiting endothelial regeneration, it exerts a protective effect against restenosis after balloon injury.
    Original languageEnglish
    Pages (from-to)H2015-25
    Number of pages11
    JournalAmerican Journal of Physiology (Heart and Circulatory Physiology)
    Volume297
    Issue number6
    DOIs
    Publication statusPublished - Dec 2009

    Keywords

    • Myocytes, Smooth Muscle
    • Animals
    • Carotid Artery Injuries
    • Apoptosis
    • Disease Models, Animal
    • Cell Proliferation
    • Cell Survival
    • Rats
    • Phosphorylation
    • Mitogen-Activated Protein Kinase 3
    • Cyclic AMP-Dependent Protein Kinases
    • Mitogen-Activated Protein Kinase 1
    • Male
    • Signal Transduction
    • ras Proteins
    • Enzyme Activation
    • Cyclic AMP
    • Proto-Oncogene Proteins c-akt
    • Endothelial Cells
    • Phosphatidylinositol 3-Kinases
    • Hyperplasia
    • Catheterization
    • Cells, Cultured
    • Muscle, Smooth, Vascular
    • Transfection
    • Rats, Wistar

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