Structural mechanisms in the abolishment of VEGF-induced microvascular hyperpermeability by cAMP.
To investigate the structural mechanisms by which elevation of the intraendothelial cAMP levels abolishes or attenuates the transient increase in microvascular permeability by vascular endothelial growth factor (VEGF), we examined cAMP effect on VEGF-induced hyperpermeability to small solute sodium fluorescein (Stokes radius = 0.45 nm) P(sodium fluorescein), intermediate-sized solute alpha-lactalbumin (Stokes radius = 2.01 nm) P(alpha-lactalbumin), and large solute albumin (BSA, Stokes radius = 3.5 nm) P(BSA) on individually perfused microvessels of frog mesenteries. After 20 min pretreatment of 2 mM cAMP analog, 8-bromo-cAMP, the initial increase by 1 nM VEGF was completely abolished in P(sodium fluorescein) (from a peak increase of 2.6+/-0.37 times control with VEGF alone to 0.96+/-0.07 times control with VEGF and cAMP), in P(alpha-lactalbumin) (from a peak increase of 2.7+/-0.33 times control with VEGF alone to 0.76+/-0.07 times control with VEGF and cAMP), and in P(BSA) (from a peak increase of 6.5+/-1.0 times control with VEGF alone to 0.97+/-0.08 times control with VEGF and cAMP). Based on these measured data, the prediction from our mathematical models suggested that the increase in the number of tight junction strands in the cleft between endothelial cells forming the microvessel wall is one of the mechanisms for the abolishment of VEGF-induced hyperpermeability by cAMP.
Fu
Bingmei M
BM
Department of Biomedical Engineering, The City College of the City University of New York, 138th St. at Convent Ave., New York, NY 10031, USA. fu@ccny.cuny.edu
Shen
Shang
S
Chen
Bin
B
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology*; D003198:Computer Simulation; D000242:Cyclic AMP / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D008833:Microcirculation / Q000187:drug effects* / Q000502:physiology*; D008954:Models, Biological; D011898:Ranidae; D013152:Splanchnic Circulation / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage*
D004338:Drug Combinations; D042461:Vascular Endothelial Growth Factor A; D000242:Cyclic AMP