Differential phosphodiesterase activity contributes to restrictive endothelial barrier function during angiogenesis

Microvasc Res. 2001 Nov;62(3):263-70. doi: 10.1006/mvre.2001.2340.

Abstract

Angiogenic endothelial hyperpermeability is abruptly diminished between days 4.5 and 5.0 of the 18-day lifespan of the chick chorioallantoic membrane. Here, we evaluated phosphodiesterase (PDE) activity during the differentiation of barrier function. At day 4.5, rolipram-mediated inhibition of cAMP-specific PDE IV reduced FITC-dextran extravasation. Moreover, inhibition of PDE III by HL 725, but not PDE I by 8-IBMX, decreased the temporal angiogenic endothelial hyperpermeability. Reduced FITC-dextran was also observed at day 4.5 after application of KT 5823, a selective inhibitor of cGMP-specific protein kinase G (PKG), LY 83583, an inhibitor of soluble guanylate cyclase, or LNMMA, an inhibitor of nitric oxide synthase. At day 5.0, Rp-cAMPS-mediated inhibition of cAMP-specific protein kinase A (PKA) diminished barrier function and interstitial accumulation of FITC-dextran was increased. In all cases, the mean widths of interendothelial separation remained uniform. Together, the results support the concept that differentiation of restrictive angiogenic endothelial barrier function in vivo includes inactivation of PDE III and PDE IV with consequent up-regulation of cAMP/PKA signaling and down-regulation of the cGMP/PKG pathway.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Allantois / blood supply
  • Allantois / ultrastructure
  • Animals
  • Capillary Permeability / drug effects
  • Capillary Permeability / physiology*
  • Cell Differentiation / drug effects
  • Chick Embryo
  • Chorion / blood supply
  • Chorion / ultrastructure
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cyclic GMP / analogs & derivatives*
  • Cyclic GMP / metabolism
  • Cyclic GMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic GMP-Dependent Protein Kinases / metabolism
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / enzymology
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / ultrastructure
  • Enzyme Inhibitors / pharmacology*
  • Image Processing, Computer-Assisted
  • Isoenzymes / metabolism
  • Microscopy, Electron
  • Neovascularization, Physiologic / physiology*
  • Phosphodiesterase Inhibitors / pharmacology
  • Phosphoric Diester Hydrolases / metabolism*
  • Rolipram / pharmacology
  • Time Factors

Substances

  • Enzyme Inhibitors
  • Isoenzymes
  • Phosphodiesterase Inhibitors
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Cyclic GMP-Dependent Protein Kinases
  • Phosphoric Diester Hydrolases
  • Cyclic GMP
  • Rolipram