New connections: Taming vascular inflammation

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Science Signaling  15 Mar 2016:
Vol. 9, Issue 419, pp. ec63
DOI: 10.1126/scisignal.aaf6710

Vascular inflammation contributes to vascular diseases, such as atherosclerosis and arteritis. This week’s issue of Science Signaling has a pair of papers that investigate how the vascular endothelial cells themselves contribute to this process by promoting either the adhesion of leukocytes to their surface where they contribute to the formation of atherosclerotic plaques or their migration through the vessel promoting inflammation, such as that seen in giant cell arteritis. Reelin is a glycoprotein produced by the liver and released into the circulation where it regulates blood clotting. Endothelial cells lining the blood vessels have receptors for Reelin. Ding et al. found that mice globally deficient in Reelin or lacking Reelin produced by the liver were protected from diet-induced atherosclerosis. This protective effect was associated with decreased abundance of the adhesion proteins VCAM1, ICAM1, and E-selectin on the endothelial cell surface, which reduced the binding of monocytes to the endothelial cells, a critical first step in the inflammatory response that promotes atherosclerosis. Blocking the proadhesion activity of Reelin on endothelial cells may prevent atherosclerosis or complement existing strategies. In research published in 2015, Galvani et al. examined the role of a different endothelial cell receptor in atherosclerosis, the sphingosine 1-phosphate receptor (S1P1). In this case, studies with mice with an endothelial cell–specific knockout in S1P1 demonstrated a protective role, rather than a proinflammatory role, for this receptor. S1P, a lipid mediator that is carried in the blood bound to various chaperone protein complexes, elicited chaperone-specific signaling in the endothelial cells. Of particular relevance to atherosclerosis, S1P bound to lipoprotein ApoM in the context of the high-density lipoprotein (HDL) complex to reduce the abundance of ICAM-1. Thus, this pathway may explain the cardiovascular benefits of HDL, the so-called good cholesterol. Espígol-Frigolé et al. reported that a single subunit p19 of a normally dimeric secreted cytokine IL-23 acted from inside the endothelial cells of capillaries from patients with giant cell arteritis to increase the abundance of ICAM-1 and VCAM-1. This process involved binding of p19 to one of the cytokine receptor subunits gp130 and promoted leukocyte attachment to endothelial cells and their transendothelial cell migration. These studies show that understanding how the “stickiness” of endothelial cells is regulated can aid in the development of therapies to treat vascular disease.

Y. Ding, L. Huang, X. Xian, I. S. Yuhanna, C. R. Wasser, M. Frotscher, C. Mineo, P. W. Shaul, J. Herz, Loss of Reelin protects against atherosclerosis by reducing leukocyte–endothelial cell adhesion and lesion macrophage accumulation. Sci. Signal. 9, ra29 (2016). [Abstract]

G. Espígol-Frigolé, E. Planas-Rigol, H. Ohnuki, O. Salvucci, H. Kwak, S. Ravichandran, B. Luke, M. C. Cid, G. Tosato, Identification of IL-23p19 as an endothelial proinflammatory peptide that promotes gp130-STAT3 signaling. Sci. Signal. 9, ra28 (2016). [Abstract]

S. Galvani, M. Sanson, V. A. Blaho, S. L. Swendeman, H. Obinata, H. Conger, B. Dahlbäck, M. Kono, R. L. Proia, J. D. Smith, T. Hla, HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation. Sci. Signal. 8, ra79 (2015). [Abstract]