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Direct ANP inhibition of hypoxia-induced inflammatory pathways in pulmonary microvascular and macrovascular endothelial monolayers

¹Department of Biomedical Sciences, College of Veterinary and Biomedical Sciences, Colorado State University, Fort Collins, and ²Department of Anesthesiology, University of Colorado Health Science Center, Denver, Colorado

Submitted 5 August 2004 ; accepted in final form 16 December 2004

Atrial natriuretic peptide (ANP) has been shown to reduce hypoxia-induced pulmonary vascular leak in vivo, but no explanation of a mechanism has been offered other than its vasodilatory and natriuretic actions. Recently, data have shown that ANP can protect endothelial barrier functions in TNF--stimulated human umbilical vein endothelial cells. Therefore, we hypothesized that ANP actions would inhibit pulmonary vascular leak by inhibition of TNF- secretion and F-actin formation. Bovine pulmonary microvascular (MVEC) and macrovascular endothelial cell (LEC) monolayers were stimulated with hypoxia, TNF-, or bacterial endotoxin (LPS) in the presence or absence of ANP, and albumin flux, NF-B activation, TNF- secretion, p38 mitogen-activated protein kinase (MAPK), and F-actin (stress fiber) formation were assessed. In Transwell cultures, ANP reduced hypoxia-induced permeability in MVEC and TNF--induced permeability in MVEC and LEC. ANP inhibited hypoxia and LPS increased NF-B activation and TNF- synthesis in MVEC and LEC. Hypoxia decreased activation of p38 MAPK in MVEC but increased activation of p38 MAPK and stress fiber formation in LEC; TNF- had the opposite effect. ANP inhibited an activation of p38 MAPK in MVEC or LEC. These data indicate that in endothelial cell monolayers, hypoxia activates a signal cascade analogous to that initiated by inflammatory agents, and ANP has a direct cytoprotective effect on the pulmonary endothelium other than its vasodilatory and natriuretic properties. Furthermore, our data show that MVEC and LEC respond differently to hypoxia, TNF--stimulation, and ANP treatment.

altitude; atrial natriuretic peptide; endothelial cell permeability; tumor necrosis factor-; lipopolysaccharide

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