The pathogenic role of angiogenesis in rheumatoid arthritis

Abstract

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.

Advanced nanomedicine for rheumatoid arthritis treatment: focus on active targeting

“…The second limiting factor was the inflamed vascular endothelium. Under inflammatory stimuli, endothelial cells were activated to release matrix-degrading enzymes to digest the basal membrane, then emigrated and divided to form primitive angiotubes, which eventually developed into angiogenesis [5]. The circulating nanomedicine could either target to this abnormal vasculature to eliminate the angiogenesis or further transfer across the endothelium to enter the joint cavity and relieve other rheumatic symptoms such as inflammation.…”

“…Numerous relevant mediators like growth factors, pro-inflammatory cytokines, chemokines, cell adhesion molecules, and proteases have participated in the development of angiogenesis. Among these, the hypoxia-vascular endothelial growth factors (VEGF)-angiopoietin system plays a central role [5]. In addition, several adhesion molecules including α v β 3 integrins, E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular cell adhesion molecule-1 are over-expressed on the surface of endothelial cells [5,[7][8][9][10].…”

“…Among these, the hypoxia-vascular endothelial growth factors (VEGF)-angiopoietin system plays a central role [5]. In addition, several adhesion molecules including α v β 3 integrins, E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular cell adhesion molecule-1 are over-expressed on the surface of endothelial cells [5,[7][8][9][10]. Macrophages, abundant in the inflamed synovial membrane, possess broad proinflammatory potential and contribute considerably to inflammation and joint destruction.…”

Cellular reactions of CD3+ CD4+ CD45RO+ T-lymphocytes on dexamethason in in normal patients and in patients with with rheumatoid arthritis in vitro

“…При ýтом выявлено, что все CD3 + основных провоспа-лительных цитокинов (IL-2, IL-17, IL-21, TNFα и IFNγ), принимающих участие в патогенезе РА. Так, IL-17 и IFNγ играют ключевую роль в иници-ации РА, приводя к появлению первичных сим-птомов заболевания, усиливая воспалительный ответ [29,30], тогда как IL-21 и TNFα в большей степени участвуют в пролонгации заболевания, способствуя инфильтрации клеток в синовиаль-ные ткани с последующим разрушением сустав-ного хряща при РА [31,32].…”

“…Выявлено, что Dex ингибирует транскрипцию гена IL-2, снижая стабильность его мРНК [34]. Кроме того, ГК способны связывать транскрип-ционные факторы (NFAT, AP-1), индуцирующие ýкспрессию гена IL-2, препятствуя образованию димерных комплексов (NFAT+AP-1) и предот-вращая их прямое взаимодействие с промотор-ными областями гена [16,31]. Выявленный нами супрессорный ýффект Dex на ýкспрессию CD25-молекулы Т-клетками CD4 + может быть опосре-дован снижением аутопродукции IL-2 [10,34].…”