Constitutive eNOS-derived nitric oxide is a determinant of endothelial junctional integrity.
Basal vascular endothelial permeability is normally kept low in part by the restrictiveness of interendothelial junctions (IEJs). We investigated the possible role of nitric oxide (NO) in controlling IEJ integrity and thereby regulating basal vascular permeability. We determined the permeability of continuous endothelia in multiple murine vascular beds, including lung vasculature, of wild-type mice, endothelial nitric oxide synthase (eNOS) null mice, and mice treated with NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME). Light and electron microscopic studies revealed that L-NAME treatment resulted in IEJs opening within a few minutes with a widespread response within 30 min. We observed a 35% increase in transendothelial transport of albumin, using as tracer dinitrophenylated albumin in mouse lungs and other organs studied. To rule out the involvement of blood cells in the mechanism of increased endothelial permeability, vascular beds were flushed free of blood, treated with L-NAME, and perfused with the tracer. The open IEJs observed in these studies indicated a direct role for NO in preserving the normal structure of endothelial junctions. We also used the electron-opaque tracer lanthanum chloride to assess vascular permeability. Lanthanum chloride was presented by perfusion to various vascular beds of mice lacking NO. Open IEJs were seen only in capillary and venular endothelial segments of mice lacking NO, and there was a concomitant increase in vascular permeability to the tracer. Together, these data demonstrate that constitutive eNOS-derived NO is a crucial determinant of IEJ integrity and thus serves to maintain the low basal permeability of continuous endothelia.
Predescu
Dan
D
Department of Pharmacology, University of Illinois, College of Medicine, Chicago, 60612, USA. Predescu@uic.edu
Predescu
Sanda
S
Shimizu
Jun
J
Miyawaki-Shimizu
Kayo
K
Malik
Asrar B
AB
D000418:Albumins / Q000378:metabolism; D000818:Animals; D001808:Blood Vessels / Q000648:ultrastructure; D002199:Capillary Permeability / Q000502:physiology*; D004396:Coloring Agents; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007211:Indoles; D007365:Intercellular Junctions / Q000378:metabolism* / Q000648:ultrastructure; D008168:Lung / Q000098:blood supply; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009942:Organometallic Compounds
D000418:Albumins; D004396:Coloring Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D009942:Organometallic Compounds; D009569:Nitric Oxide; C015445:copper phthalocyanine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D019331:NG-Nitroarginine Methyl Ester