REVIEW ARTICLE The potential role of angiogenic factors in rheumatoid arthritis Gholamreza AZIZI, 1 Roobina BOGHOZIAN 2 and Abbas MIRSHAFIEY 2 1 Imam Hassan Mojtaba Hospital, Alborz University of Medical Sciences, Karaj, and 2 Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran Abstract Angiogenesis is an important phenomenon in the pathogenesis of some diseases, such as numerous types of tumors and autoimmunity, and also a number of soluble and cell-bound factors may stimulate neovascularization in inflammatory reaction processes. Here, by highlighting the significance of angiogenesis reaction in rheumatoid arthritis (RA), we will mainly focus on the role of various growth factors, cytokines, enzymes, cells, hypoxic condi- tions and transcription factors in the angiogenic process and we will then explain some therapeutic strategies based on blockage of angiogenesis and modification of the vascular pathology in RA. Key words: angiogenesis, cytokines, hypoxia, RA, VEGF. ANGIOGENESIS AND ANGIOGENIC FACTORS Angiogenesis is the growth of new capillaries from pre- existing vasculature and is classically defined as the pro- cess of development and formation of new blood vessels that occurs during the growth and development of tis- sues. It can also play a key role in several physiological events, including embryonic development, reproduc- tion, tissue repair and normal wound healing. 1,2 There are two separate pathological angiogenesis: 1 Excessive angiogenesis; in some diseases the excessive angiogenesis plays an essential role in pathological processes, such as diabetic retinopathy, rheumatoid arthritis (RA), osteoarthritis, psoriasis, atherosclerosis and neoplasms. 3 In many cancers, following tumor growth, neovascularization could be a negative prog- nostic indicator signifying aggressive disease and increased metastasis. 4 2 Insufficient angiogenesis; delayed wound healing, and also the lack of angiogenesis, may lead to cardiac failure and limb ischemia as well as stroke. 1,2 Angiogenesis is a complex multistep process requiring stimulation of proliferation and migration of endothe- lial cells (ECs). It involves a series of coordinated events: activation of ECs, disruption of vascular base- ment membrane and extra-cellular surrounding matrix, migration of the ECs to distal sites, proliferation of ECs, differentiation of ECs, and subsequent formation and maturation of new blood vessels. 5 Blood vessels are composed of two interacting cell types. ECs form the inner lining of the vessel wall, and pericytes (mural cells or vascular smooth muscle cells) envelop the surface of the vascular tube. In the past decades, investigations of blood vessels had focused mainly on the ECs compo- nent, while the interest in pericytes had lagged behind. Recently, pericytes have acquired new consideration as critical contributors to angiogenesis and potential thera- peutic targets for antiangiogenic treatment. 6 Furthermore, the heterotypic interactions of pericytes and ECs and extracellular matrix (ECM) components, such as the neural cell adhesion molecule (NCAM) are critical for congregation, stability and maturation of Correspondence: Professor Abbas Mirshafiey, Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Box 6446, Tehran-14155, Iran. Email: mirshafiey@tums.ac.ir © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd International Journal of Rheumatic Diseases 2014; 17: 369–383