Further, there is no difference in HUVEC, HUAEC, or HPMECs (Figures 1(e)C1(g))

Further, there is no difference in HUVEC, HUAEC, or HPMECs (Figures 1(e)C1(g)). These findings show that flow GSK-LSD1 dihydrochloride conditions downregulate the basal expression of CX3CL1 but not that of CXCL16 in endothelial cells from different vascular beds. 3.2. to endothelial cells was observed. This adhesion was in part mediated by transmembrane CX3CL1 as demonstrated with a neutralizing antibody. By contrast, no CX3CL1-dependent adhesion to stimulated endothelium was observed at high shear stress. Thus, during early stages of vascular inflammation, low shear stress typically seen at atherosclerosis-prone regions promotes the induction of endothelial CX3CL1 and monocytic cell recruitment, whereas physiological shear stress counteracts this inflammatory activation of endothelial cells. 1. Introduction In the body, vascular endothelial cells are constantly exposed to blood flow. The resulting laminar shear stress on the endothelial surface can largely differ in large and small arteries or veins, respectively [1, 2]. Exposure to laminar flow typically leads to an alignment of the endothelial cells in the direction of the flow, cytoskeletal rearrangements, the formation of tight endothelial cell-to-cell contacts, reduced permeability, arrest of cell proliferation, and prolonged cell survival [3C7]. These phenotypical characteristics are maintained by a transcriptional response to the flow conditions resulting in the altered expression of regulators of the vascular tone, endothelial surface molecules, and soluble mediators. Typically, endothelial NO synthase is upregulated by high shear stress, whereas endothelin-1 or vascular cell adhesion molecule-1 (VCAM-1) gene expression is downregulated [8C12]. The importance of shear stress for endothelial cell functions is highlighted by pathological processes associated with reduced or absent laminar shear stress, which can occur in GSK-LSD1 dihydrochloride vascular beds that are prone to atherosclerosis. At GATA3 branch points and curved areas such as the carotid sinus, disturbed flow including flow reversal or turbulence may occur. In these areas, the average shear stress is considerably lower and values below 1?dyn/cm2 can occur, which is 10 times lower than the average of 10?dyn/cm2 in the human vasculature and even 100 times lower compared to the microvasculature [1, 2, 13]. These areas are characterized by an absence of preferential endothelial alignment and are predisposed to develop atherosclerotic lesions. An early step in the development of atherosclerotic lesions is the production of proinflammatory chemokines and adhesion molecules by the vascular wall. This results in increased binding of inflammatory leukocytes, especially monocytes, from the blood to the vascular surface. The adherent monocytes become activated and migrate into the vascular wall where they contribute to the lesion development by production of inflammatory mediators, by uptake of lipids, and by differentiation into macrophages and finally foam cells [14]. Monocyte recruitment to atherosclerotic lesions is driven by several chemotactic cytokines including CX3CL1 also termed fractalkine [15]. CX3CL1 is special within the chemokine family, since it is synthesized as a transmembrane molecule that is expressed on the endothelial cell surface [16]. As such, the chemokine can interact with its receptor CX3CR1, which is expressed on monocytic cells, T cell subsets, and NK cells [17]. Thereby, CX3CL1 can promote cell adhesion without the need of further activation [18]. Stimulation of cultured endothelial cells with proinflammatory mediators leads to enhanced expression of CX3CL1, which then promotes adhesion of monocytic cells. Thereafter, the activation of CX3CR1 can induce cell migration of the adherent monocytes leading to transmigration through the endothelial cell layer [19]. In addition to its activity as transmembrane adhesion molecule, CX3CL1 can act as classical chemoattractant for leukocytes when it is shed from the cell surface by the activity of ADAM10 (short for a disintegrin and metalloproteinase) and ADAM17 [20, 21]. Besides CX3CL1, the only other transmembrane chemokine is CXCL16, which is also expressed GSK-LSD1 dihydrochloride and shed by endothelial cells [22, 23] and implicated in the recruitment of T cells to the inflamed vasculature [24, 25]. It has been shown that CX3CL1 is highly expressed at vascular sites, which are prone to lesion development and serve as one of the critical mediators driving monocytic cell recruitment to these lesions [26, 27]. In carotid arteries, CX3CL1 expression is highest at regions of low laminar shear stress [28]. This may suggest that the upregulation of the chemokine can be a direct.