Angiogenesis is the formation of new capillaries from pre-existing vasculature, which plays a critical role in the pathogenesis of several inflammatory autoimmune diseases such as rheumatoid arthritis (RA), spondyloarthropathies, psoriasis, systemic lupus erythematosus, systemic sclerosis and atherosclerosis. In RA, excessive migration of circulating leukocytes into the inflamed joint necessitates formation of new blood vessels to provide nutrients and oxygen to the hypertrophic joint. The dominance of the pro-angiogenic factors over the endogenous angiostatic mediators triggers angiogenesis. In this review article, we highlight the underlying mechanisms by which cells present in the RA synovial tissue are modulated to secrete pro-angiogenic factors. We focus on the significance of pro-angiogenic factors such as growth factors, hypoxia inducible factors, cytokines, chemokines, matrix metalloproteinase and adhesion molecules on RA pathogenesis. As pro-angiogenic factors are primarily produced from RA synovial tissue macrophages and fibroblasts, we emphasize the key role of RA synovial tissue lining layer in maintaining synovitis through neovascularization. Lastly, we summarize the specific approaches utilized to target angiogenesis. We conclude that the formation of new blood vessels plays an indispensable role in RA progression. However since the function of several pro-angiogenic mediators is cross regulated, discovering novel approaches to target multiple cascades or selecting an upstream cascade that impairs the activity of a number of pro-angiogenic factors may provide a promising strategy for RA therapy.

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Blood flow interactions with the vascular endothelium represent a specialized example of mechanical regulation of cell function that has important physiological and pathological cardiovascular consequences. The endothelial monolayer in vivo acts as a signal transduction interface for forces associated with flowing blood (hemodynamic forces) in the acute regulation of artery tone and chronic structural remodeling of arteries, including the pathology of atherosclerosis. Mechanisms related to spatial relationships at the cell surfaces and throughout the cell that influence flow-mediated endothelial mechanotransduction are discussed. In particular, flow-mediated ion channel activation and cytoskeletal dynamics are considered in relation to topographic analyses of the luminal and abluminal surfaces of living endothelial cells.

Angiogenesis is an early and a critical event in the pathogenesis of rheumatoid arthritis (RA). Neovascularization is dependent on endothelial cell activation, migration and proliferation, and inhibition of angiogenesis may provide a novel therapeutic approach in RA. In this study, we document a novel role of IL-17 in mediating angiogenesis. Local expression of IL-17 in mouse ankles increases vascularity. We further demonstrate that IL-17 is angiogenic by showing its ability to promote blood vessel growth in Matrigel plugs in vivo. Additionally, IL-17, in concentrations present in the RA joint, induces human lung microvascular endothelial cell (HMVEC) migration mediated through the PI3K/AKT1 pathway. Furthermore, suppression of the PI3K pathway markedly reduces IL-17–induced tube formation. We also show that both IL-17–induced HMVEC chemotaxis and tube formation are mediated primarily through IL-17 receptor C. Neutralization of either IL-17 in RA synovial fluids or IL-17 receptor C on HMVECs significantly reduces the induction of HMVEC migration by RA synovial fluid. Finally, RA synovial fluid immunoneutralized with anti–IL-17 and antivascular endothelial growth factor does not reduce HMVEC migration beyond the effect detected by immunodepleting each factor alone. These observations identify a novel function for IL-17 as an angiogenic mediator in RA, supporting IL-17 as a therapeutic target in RA.

Angiogenesis is an important aspect of the vasculoproliferation found in the rheumatoid arthritic (RA) pannus. We have previously implicated members of the CXC chemokine family as potent angiogenic mediators in RA. We investigated the possibility that the sole member of the CX 3 C chemokine family, fractalkine (fkn), induces angiogenesis and that fkn might mediate angiogenesis in RA. Recombinant human fkn significantly induced migration of human dermal microvascular endothelial cells (HMVECs), a facet of the angiogenic response, in the pmol/L range in a concentration-dependent manner (P < 0.05). Fkn also induced the formation of significantly more endothelial tubes on Matrigel than did a negative control (P < 0.05). Fkn significantly induced 2.3-fold more blood vessel growth than control in the in vivo Matrigel plug assays (P < 0.05). We identified HMVEC expression of the fkn receptor, CX 3 CR1. Next, we determined if RA synovial fluid (SF)-induced angiogenesis was fkn-dependent. SFs from six RA patients immunodepleted of soluble fkn induced 56% less migration of HMVECs than did sham-depleted RA SFs (P < 0.05).

Objective. To examine cytokine and chemokine production during the evolution of rat adjuvant-induced arthritis (AIA), a model of rheumatoid arthritis. Methods. Clinical and laboratory assessment of the course of AIA was performed over a 47-day period. Levels of the cytokines tumor necrosis factor (TNF), interleukin-1 (IL-1), and IL-6, as well as levels of the chemokines macrophage inflammatory protein 1 (MIP-1) and JE, the murine homolog of monocyte chemoattractant protein 1, were determined by enzyme-linked immunosorbent assay in the sera and joints of AIA and control rats. Synovia from AIA rats were (immuno)histochemically analyzed. Results of cytokine and chemokine measurements were correlated with clinical and laboratory markers of inflammation and histology. Results. Early (before day 14 post adjuvant injection) and later phases of AIA could be distinguished. Cytokine and chemokine production was increased in AIA versus control rats. The production of TNF, IL-1, MIP-1, and, as determined earlier, epithelial neutrophil-activating peptide 78-like protein was abundant prior to and during the course of AIA, while that of IL-6 and JE was elevated in the late phase of AIA. Cytokine and chemokine levels were correlated with the clinical symptoms of arthritis and blood neutrophil counts. Joint levels of IL-1 showed correlation with synovial lining proliferation and neutrophil ingress into AIA synovium. Conclusion. Cytokines and chemokines are involved in the clinical, laboratory, and histologic changes underlying AIA. The production of these mediators may be temporally and spatially regulated. These findings may be important for the optimal timing of cytokine and chemokine targeting.

Objective. To characterize the expression of CCL19 and CCL21 in rheumatoid arthritis (RA) synovial tissue (ST) and to examine their regulation and pathogenetic role in macrophages and RA ST fibroblasts.Methods. Expression of CCL19 and CCL21 in RA and normal ST was demonstrated by immunohistochemistry analysis. CCL19 and CCL21 levels in synovial fluid (SF) from patients with osteoarthritis (OA), juvenile idiopathic arthritis, psoriatic arthritis (PsA), and RA were quantified by enzyme-linked immunosorbent assay (ELISA). Regulation of CCL19 and CCL21 expression in in vitro-differentiated RA peripheral blood macrophages as well as RA ST fibroblasts was determined by real-time reverse transcription-polymerase chain reaction. Proangiogenic factor production in CCL19-and CCL21-activated in vitro-differentiated peripheral blood macrophages and RA ST fibroblasts was examined by ELISA.Results. CCL19 and CCL21 were elevated in RA ST compared to tissue from normal controls. Levels of CCL19 and CCL21 were greatly increased in RA and PsA SF versus OA SF. In RA macrophages and fibroblasts, expression of CCL19 was increased by stimulation with lipopolysaccharide, tumor necrosis factor ␣ (TNF␣), and interleukin-1␤ (IL-1␤). However, CCL21 expression was modulated only by IL-1␤ in RA fibroblasts, and by TNF␣ and RA SF in RA macrophages. CCL19 and CCL21 activation induced vascular endothelial growth factor and angiotensin I (Ang I) production in RA ST fibroblasts and secretion of IL-8 and Ang I from macrophages.Conclusion. The findings of the present study identify, for the first time, regulators of CCL19 and CCL21 in RA fibroblasts and in vitro-differentiated RA peripheral blood macrophages and demonstrate a novel role of CCL19/CCL21 in angiogenesis in RA.Rheumatoid arthritis (RA) is a chronic systemic disorder characterized by the development of new capillaries that are involved in the infiltration of inflammatory cells which results in synovial hyperplasia and progressive destruction of cartilage and bone. Synovial tissue (ST) lining consists of macrophages and fibroblasts that have profound effects in the destructive process in RA, via production of proinflammatory cytokines, chemokines, and proangiogenic factors (1,2).CCL19 and CCL21 and their corresponding receptor CCR7 are involved in organizing the thymic architecture and homing of various subpopulations of T cells and antigen-presenting dendritic cells to lymph nodes (3). CCL19 is expressed in lymph nodes and fibroblastic reticular cells in the T cell-rich area, whereas CCL21 is secreted from fibroblastic reticular cells and high endothelial venules (4,5). Although CCL19 and CCL21 have similar affinity for CCR7, ligation of these chemokines mediates different signaling effects. Previous studies have shown that while

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