Adenylate Cyclase/Protein Kinase A Signaling Pathway Enhances Angiogenesis Through Induction of Vascular Endothelial Growth Factor In Vivo.

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  • Amano Hideki
    Department of Pharmacology, Kitasato University School of Medicine
  • Ando Kao
    Department of Pharmacology, Kitasato University School of Medicine
  • Minamida Satoshi
    Department of Pharmacology, Kitasato University School of Medicine
  • Hayashi Izumi
    Department of Pharmacology, Kitasato University School of Medicine
  • Ogino Michiko
    Department of Pharmacology, Kitasato University School of Medicine
  • Yamashina Shohei
    Department of Anatomy, Kitasato University School of Medicine
  • Yoshimura Hirokuni
    Department of Thoracic Surgery, Kitasato University School of Medicine
  • Majima Masataka
    Department of Pharmacology, Kitasato University School of Medicine

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We previously reported that endogenous prostaglandins (PGs) may increase cAMP facilitated angiogenesis through the induction of vascular endothelial growth factor (VEGF) in rat sponge implantation models. In the present experiment, we tested whether or not adenylate cyclase / protein kinase A (AC/PKA)-dependent VEGF induction enhanced angiogenesis in this model. Topical daily injections of 8-bromo-cAMP enhanced angiogenesis in a dose-dependent manner. Forskolin, an activator of AC, also facilitated angiogenesis as did amrinone, an inhibitor of phosphodiesterase. VEGF induction was confirmed by the increased levels in the fluids in the sponge matrix after topical injection of 8-bromo-cAMP. Immunohistochemical investigation further revealed the VEGF-expressed cells in the sponge granulation tissues to be fibroblasts, and the intensity of positive reactions was enhanced by 8-bromo-cAMP, forskolin and amrinone. Angiogenesis without topical injections of the above compounds was suppressed by SQ22,536, an inhibitor for AC, or H-89, an inhibitor for PKA, with concomitant reductions in VEGF levels. Daily topical injections of neutralizing antibody or anti-sense oligonucleotide against VEGF significantly suppressed angiogenesis. PGE2-induced angiogenesis was suppressed with SQ22,536 or H-89. These results suggested that AC/PKA-dependent induction of VEGF certainly enhanced angiogenesis and that pharmacological tools for controlling this signaling pathway may be able to facilitate the management of conditions involving angiogenesis.

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