Abstract
αB-crystallin is a small heat shock protein, which has pro-angiogenic properties by increasing survival of endothelial cells and secretion of vascular endothelial growth factor A. Here we demonstrate an additional role of αB-crystallin in regulating vascular function, through enhancing tumor necrosis factor α (TNF-α) induced expression of endothelial adhesion molecules involved in leukocyte recruitment. Ectopic expression of αB-crystallin in endothelial cells increases the level of E-selectin expression in response to TNF-α, and enhances leukocyte–endothelial interaction in vitro. Conversely, TNF-α-induced expression of intercellular adhesion molecule 1, vascular cell adhesion molecule 1 and E-selectin is markedly inhibited in endothelial cells isolated from αB-crystallin-deficient mice. This is associated with elevated levels of IκB in αB-crystallin deficient cells and incomplete degradation upon TNF-α stimulation. Consistent with this, endothelial adhesion molecule expression is reduced in inflamed vessels of αB-crystallin deficient mice, and leukocyte rolling velocity is increased. Our data identify αB-crystallin as a new regulator of leukocyte recruitment, by enhancing pro-inflammatory nuclear factor κ B-signaling and endothelial adhesion molecule expression during endothelial activation.Electronic supplementary materialThe online version of this article (doi:10.1007/s10456-013-9367-4) contains supplementary material, which is available to authorized users.
Highlights
Overexpression of aB-crystallin in Human Umbilical Vein Endothelial Cells (HUVEC) had no significant effects on cell proliferation (Fig S1a) To determine if aB-crystallin expression affects expression of endothelial adhesion molecules, we treated pgk:cryab and pgk:ev HUVEC with tumor necrosis factor a (TNF-a) and analyzed surface expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and E-selectin by
Various types of endothelial cells, including human dermal microvascular endothelial cells (HDMEC) and bovine capillary endothelial cells (BCE), express aB-crystallin in culture, while expression is not detectable in e.g. HUVEC. aB-crystallin expression is up-regulated in tumor associated blood vessels [1, 17], but the vascular expression pattern of aB-crystallin in different organs, vascular beds, and different types of pathologies has not been thoroughly investigated
We have previously shown that aB-crystallin is up-regulated during VEGF-A-induced tubular morphogenesis and promotes angiogenesis by inhibiting caspase-3 activation in endothelial cells, increasing cell survival [1]
Summary
A central step in the inflammatory process is the activation of endothelial cells that mediate recruitment of leukocytes from the blood stream into the inflamed tissue Proinflammatory cytokines such as tumor necrosis factor a (TNF-a) are produced by tissue resident immune cells, inducing activation of local endothelial cells through the nuclear factor j B (NF-jB) pathway, which in endothelial cells regulates the expression of various chemokines and adhesion molecules such as E-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) [8]. Our data demonstrates that aB-crystallin has an important function during this process by enhancing TNF-a-induced activation of NF-jB-signalling and downstream activation of endothelial adhesion molecules
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