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A critical role for both CD40 and VLA5 in angiotensin Il–mediated thrombosis and inflammation
Author(s) -
Senchenkova Elena Y.,
Russell Janice,
Vital Shantel A.,
Yildirim Alper,
Orr A. Wayne,
Granger D. Neil,
Gavins Felicity N. E.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201701068r
Subject(s) - cd40 , angiotensin ii , inflammation , proinflammatory cytokine , thrombus , cremaster muscle , intravital microscopy , medicine , endocrinology , immunology , chemistry , receptor , microcirculation , biochemistry , cytotoxic t cell , in vitro
Angiotensin II (Ang‐II)–induced hypertension is associated with accelerated thrombus formation in arterioles and leukocyte recruitment in venules. The mechanisms that underlie the prothrombotic and proinflammatory responses to chronic Ang‐II administration remain poorly understood. We evaluated the role of CD40/CD40 ligand (CD40L) signaling in Ang‐II–mediated microvascular responses and assessed whether and how soluble CD40L (sCD40L) contributes to this response. Intravital video microscopy was performed to analyze leukocyte recruitment and dihydrorhodamine‐123 oxidation in postcapillary venules. Thrombus formation in cremaster muscle arterioles was induced by using the light/dye endothelial cell injury model. Wild‐type (WT), CD40 −/− , and CD40L −/− mice received Ang‐II for 14 d via osmotic minipumps. Some mice were treated with either recombinant sCD40L or the VLA5 (very late antigen 5; α5β1) antagonist, ATN‐161. Our results demonstrate that CD40 −/− , CD40L −/− , and WT mice that were treated with ATN‐161 were protected against the thrombotic and inflammatory effects of Ang‐II infusion. Infusion of sCD40L into CD40 −/− or CD40L −/− mice restored the prothrombotic effect of Ang‐II infusion. Mice that were treated with ATN‐161 and infused with sCD40L were protected against accelerated thrombosis. Collectively, these novel findings suggest that the mechanisms that underlie Ang‐II–dependent thrombotic and inflammatory responses link to the signaling of CD40L via both CD40 and VLA5.—Senchenkova, E. Y., Russell, J., Vital, S. A., Yildirim, A., Orr, A. W., Granger, D. N., Gavins, F. N. E. A critical role for both CD40 and VLA5 in angiotensin II‐mediated thrombosis and inflammation. FASEB J. 32, 3448–3456 (2018). www.fasebj.org