The phosphodiesterase 5 inhibitor sildenafil stimulates angiogenesis through a protein kinase G/MAPK pathway

Anastasia Pyriochou, Zongmin Zhou, Vasiliki Koika, Christos Petrou, Paul Cordopatis, William C. Sessa, Andreas Papapetropoulos

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

cGMP-degrading pathways have received little attention in the context of angiogenesis. In the present study we set out to determine whether cGMP-specific phosphodiesterase 5 (PDE5) inhibition affects new blood vessel growth. Incubation of chicken chorioallantoic membranes (CAMs) in vivo with sildenafil increased vascular length in a dose-dependent manner. Moreover, incubation of cultured endothelial cells (ECs) with the PDE5 inhibitor promoted proliferation, migration, and organization into tube-like structures. The effects of sildenafil on the angiogenesis-related properties of EC could be blocked by pre-treatment with the soluble guanylyl cyclase (sGC) inhibitor ODQ or the protein kinaseG (PKG) 1 inhibitor DT-3. In addition, over-expression of sGC in EC led to an enhanced growth and migratory response to sildenafil. To study the signaling pathways implicated in the sildenafil-stimulated angiogenic responses we determined the phosphorylation status of mitogen-activated protein kinase (MAPK) members. Incubation of cells with sildenafil increased both extracellular signal regulated kinase 1/2 (ERK 1/2) and p38 phosphorylation in a time-dependent manner. Inhibition of MEK by PD98059 and p38 with SB203580 blocked sildenafil-induced proliferation and migration, respectively, suggesting that these MAPK members are downstream of PDE5 and mediate the angiogenic effects of sildenafil. PDE5 inhibitors could, thus, be used in disease states where neo-vessel growth is desired.

Original languageEnglish (US)
Pages (from-to)197-204
Number of pages8
JournalJournal of Cellular Physiology
Volume211
Issue number1
DOIs
StatePublished - Apr 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)
  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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