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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., (Copyright 2001 Academic Press.)

Intussusceptive microvascular growth is a new mode of capillary network growth originally described in the lungs of rabbits and rats. It constitutes an alternative to endothelial sprouting. The capillary network grows by insertion of new intercapillary meshes with dimensions around 1.5 microns called tissue pillars or posts. In a recent investigation, growth by intussusception was demonstrated in the chicken chorioallantoic membrane (CAM). In the present study the first of several modes of its implementation can now be presented in the CAM by in vivo video microscopy and analyses of light and electron microscopic serial sections: Cores of tissue pillars containing collagen fibrils ensheathed by extensions of endothelial-like cells will form within the tips of vertically running tissue folds that project into the capillary lumen. Due to retraction of tissue toward the intercapillary space the fold is thinning. Finally, the pillar's core is connected to its fold by a very slender extension of a single endothelial cell. Cell membrane fusion within that slender membrane-like structure causes subsequent separation of the pillar from its fold throughout an increasing vertical distance. This mechanism allows for expansion of the capillary network into the surrounding tissue, leaving behind tissue pillars as remnants of folds.