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Journals AJP - Heart and Circulatory Physiology Volume 297 Issue 6

Abstract cAMP inhibits proliferation in most cell types, triggering different and sometimes opposing molecular pathways. p85α (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 p85α 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 p85α on neointimal hyperplasia and endothelial healing after balloon injury in vivo. Plasmid constructs carrying wild-type and PKA-modified p85α were employed in VSMCs and ECs in vitro and after balloon injury in rat carotid arteries in vivo. cAMP/PKA reduced VSMC proliferation through p85α phosphorylation. Transfected PKA-activated p85α binds p21 ras , reducing ERK1/2 activation and VSMC proliferation in vitro. In contrast, EC proliferation inhibition by cAMP is independent from PKA modification of p85α and ERK1/2 inhibition; indeed, PKA-activated p85α did not inhibit per se ERK1/2 activation and proliferation in ECs in vitro. Interestingly, cAMP reduced both VSMC and EC apoptotic death through p85α phosphorylation. Accordingly, PKA-activated p85α triggered Akt activation, reducing both VSMC and EC apoptosis in vitro. Finally, compared with controls, vascular gene transfer of PKA-activated p85α significantly reduced neointimal formation after balloon injury in rats, without inhibiting endothelial regeneration of the injured arterial segment. In conclusions, PKA-activated p85α 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. smooth muscle cells endothelial cells adenosine 3′,5′-cyclic monophosphate gene therapy Footnotes Copyright © 2009 the American Physiological Society

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

More Info
  • Publisher American Physiological Society
  • Copyright Copyright © 2011 the American Physiological Society
  • ISSN 0363-6135
  • eISSN 1522-1539
  • D.O.I. 10.1152/ajpheart.00738.2009
  • Publisher site Get PDF  

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