Cyclic GMP-mediated macromolecular extravasation from angiogenic microvessels in vivo.
Previously, we reported an abrupt reduction in chick chorioallantoic membrane (CAM) microvascular permeability to macromolecules between days 4.5 and 5.0 of the 21-day gestation. Further, exogenous activation of the cAMP pathway at day 4.5 served to restrict normal macromolecular extravasation. Here, we evaluated the influence of the cGMP pathway on macromolecular efflux at day 5.0. Zaprinast (10(-4) M), a selective inhibitor of the cGMP-specific phosphodiesterase (PDE V), acutely increased basal levels of FITC-dextran 40 extravasation. Further, the cGMP analogue, 8 br-cGMP (10(-4) and 10(-3) M) and the soluble guanylate cyclase activator, sodium nitroprusside (SNP, 10(-5) and 10(-4) M) increased tracer extravasation in a dose-dependent fashion. The cGMP-mediated increase was not associated with gap formation along the junctional clefts, however, vesiculo-vacuolar structures were characteristic of CAM endothelial ultrastructure. KT 5823 (10(-5) M), the highly selective protein kinase G (PKG) inhibitor, also served to increase basal tracer extravasation. The nonselective PDE inhibitor, IBMX (10(-4) M) had no effect alone, but reduced the permeability effects of both 8 br-cGMP and SNP. Rolipram (10(-4) M), a selective PDE IV inhibitor, on the other hand, potentiated the effect of 8 br-cGMP. These results serve to suggest that cAMP degradation, rather than PKG activation, is a principal component of the cGMP-mediated increase in CAM endothelial permeability in vivo.
Department of Anatomy, Cell Biology, and Injury Sciences UMDNJ-New Jersey Medical School Newark, 07103, USA.
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D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000482:Allantois / Q000098:blood supply; D000818:Animals; D002199:Capillary Permeability / Q000502:physiology*; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008833:Microcirculation / Q000196:embryology / Q000378:metabolism / Q000648:ultrastructure; D008854:Microscopy, Electron; D018919:Neovascularization, Physiologic; D009599:Nitroprusside / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011688:Purinones / Q000494:pharmacology; D015398:Signal Transduction
D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D009599:Nitroprusside; C016276:8-bromocyclic GMP; D000242:Cyclic AMP; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C011145:zaprinast; D006152:Cyclic GMP