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A Pivotal Role of Endothelial-Specific NF-B Signaling in the Pathogenesis of Septic Shock and Septic Vascular Dysfunction¹

Jianqiang Ding^2,*,, Dongmei Song^2,*,, Xiaobing Ye^2,*, and Shu Fang Liu^3,*,

^* Centers for Heart and Lung Research, and Immunology and Inflammation, Feinstein Institute for Medical Research, and Division of Pulmonary and Critical Care Medicine, Long Island Jewish Medical Center, New Hyde Park, NY 11040

Although the role of NF-B in the pathogenesis of sepsis and septic shock has been extensively studied, little is known about the causative contribution of endothelial-intrinsic NF-B to these pathological processes. In this study, we used transgenic (TG) mice (on FVB genetic background) that conditionally overexpress the NF-B inhibitor, mutant I-B, selectively on endothelium and their transgene-negative littermates (wild type (WT)) to define the causative role of endothelial-specific NF-B signaling in septic shock and septic vascular dysfunction. In WT mice, LPS challenge caused systemic hypotension, a significantly blunted vasoconstrictor response to norepinephrine, and an impaired endothelium-dependent vasodilator response to acetylcholine, concomitant with a markedly increased aortic inducible NO synthase expression, significantly elevated plasma and aortic levels of nitrite/nitrate, increased aortic TNF- expression, and decreased aortic endothelial NO synthase (eNOS) expression. In TG mice whose endothelial NF-B was selectively blocked, LPS caused significantly less hypotension and no impairments in vasoconstrictor and endothelium-dependent vasodilator responses, associated with significantly reduced aortic inducible NO synthase expression, decreased plasma and aortic levels of nitrite/nitrate, reduced aortic TNF- expression, and increased aortic eNOS expression. TNF- knockout mice prevented LPS-induced eNOS down-regulation. WT mice subjected to cecal ligation and puncture showed significant systemic hypotension, which was prevented in TG mice. Our data show that selective blockade of endothelial-intrinsic NF-B pathway is sufficient to abrogate the cascades of molecular events that lead to septic shock and septic vascular dysfunction, demonstrating a pivotal role of endothelial-specific NF-B signaling in the pathogenesis of septic shock and septic vascular dysfunction.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant GM063907 and the Faculty Award Program of the Feinstein Institute for Medical Research.

² J.D., D.S., and X.Y. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Shu Fang Liu, Long Island Jewish Medical Center, 270-05 76th Avenue, Research Building, RM B371, New Hyde Park, NY 11040. E-mail address: Sliu{at}lij.edu

⁴ Abbreviations used in this paper: iNOS, inducible NO synthase; Ach, acetylcholine; CLP, cecal ligation and puncture; Con, control; EC, endothelial cell; eNOS, endothelial NO synthase; I-Bmt, mutant I-B; KO, knockout; MBP, mean arterial blood pressure; NE, norepinephrine; SNP, sodium nitroprusside; VSMC, vascular smooth muscle cell; WT, wild type.