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Endothelial nitric oxide synthase regulates microvascular hyperpermeability in vivo
Author(s) -
Hatakeyama Takuya,
Pappas Peter J.,
Hobson Robert W.,
Boric Mauricio P.,
Sessa William C.,
Durán Walter N.
Publication year - 2006
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2006.108175
Subject(s) - enos , nitric oxide , cremaster muscle , mesenteries , nitric oxide synthase , vascular permeability , in vivo , vasodilation , chemistry , nitric oxide synthase type iii , medicine , endocrinology , endothelium , pharmacology , microcirculation , biology , anatomy , microbiology and biotechnology
Nitric oxide (NO) is an important regulator of blood flow, but its role in permeability is still challenged. We tested in vivo the hypotheses that: (a) endothelial nitric oxide synthase (eNOS) is not essential for regulation of baseline permeability; (b) eNOS is essential for hyperpermeability responses in inflammation; and (c) molecular inhibition of eNOS with caveolin‐1 scaffolding domain (AP‐Cav) reduces eNOS‐regulated hyperpermeability. We used eNOS‐deficient (eNOS−/−) mice and their wild‐type control as experimental animals, platelet‐activating factor (PAF) at 10 −7 m as the test pro‐inflammatory agent, and integrated optical intensity (IOI) as an index of microvascular permeability. PAF increased permeability in wild‐type cremaster muscle from a baseline of 2.4 ± 2.2 to a peak net value of 84.4 ± 2.7 units, while the corresponding values in cremaster muscle of eNOS−/− mice were 1.0 ± 0.3 and 15.6 ± 7.7 units ( P < 0.05). Similarly, PAF increased IOI in the mesentery of wild‐type mice but much less in the mesentery of eNOS−/− mice. PAF increased IOI to comparable values in the mesenteries of wild‐type mice and those lacking the gene for inducible NOS (iNOS). Administration of AP‐Cav blocked the microvascular hyperpermeability responses to 10 −7 m PAF. We conclude that: (1) baseline permeability does not depend on eNOS; (2) eNOS and NO are integral elements of the signalling pathway for the hyperpermeability response to PAF; (3) iNOS does not affect either baseline permeability or hyperpermeability responses to PAF; and (4) caveolin‐1 inhibits eNOS regulation of microvascular permeability in vivo . Our results establish eNOS as an important regulator of microvascular permeability in inflammation.