[26, 56, 57] Emerging evidence suggests that fluid and serum VEGF levels not only are elevated in RA patients with hypoxic conditions but also by pro-inflammatory cytokines IL-1 and TNF-α.[58] Currently, VEGF and its receptors are the best characterized system in the angiogenesis www.selleckchem.com/products/MLN-2238.html regulation of rheumatoid joints. The VEGFRs on EC membranes consist of the tyrosine kinases VEGFR-1 (Flt-1), VEGFR-2 (Flk-1/KDR) and VEGFR-3 (Flt-4). KDR is a main mediator of angiogenic,

mitogenic and permeability-enhancing effects of VEGF. Moreover, KDR is up-regulated in response to hypoxia, a main inducer of VEGF gene transcription.[59] It is demonstrated that hypoxia stimulated VEGF-A (the most important member of the VEGF family) and VEGFR-1 expression decrease VEGFR-2 levels in ECs. During hypoxic conditions, plasma membrane VEGFR-1 levels are elevated, while VEGFR-2 levels are depleted. One functional consequence of hypoxia is a decrease in VEGF-A-stimulated and VEGFR-2-regulated intracellular signaling along with lowered EC NOS activation. In addition,

the capillary, arterial and venous ECs subjected to hypoxia display a decreased cell migration in response to VEGF-A. A mechanistic elucidation is that VEGFR-1/VEGFR-2 ratio is substantially increased during hypoxia to obstruct VEGF-A-stimulated and VEGFR-2 regulated endothelial responses to magnify cell recovery and viability.[60] In another study, Eubank et al. in 2011 showed that hypoxia can selectively stimulate anti-angiogenic molecule expression in mononuclear

phagocytes in a granulocyte macrophage colony-stimulating factor (GM-CSF) SB431542 enriched environment. The soluble VEGFR-1 (sVEGFR-1) is one of these molecules that act as a negative regulator for VEGF activity through VEGFR-2. Therefore, anti-angiogenic molecules can effect proliferation, migration and survival of ECs.[61] Placenta growth factor is another angiogenic factor and highly homologous with VEGF. PLGF can exert its angiogenic RANTES effect by synergizing with VEGF. However, it does not have an effect on lymphatic vessel functionality.[62, 63] Furthermore, PLGF can promote the production of VEGF from monocytes and macrophages.[64] It has been recently reported that PLGF is highly expressed in synovial tissue and enhances the production of pro-inflammatory cytokines, including TNF-α and IL-6.[65] Oncostatin M (OSM) belongs to the IL-6 subfamily and is mostly produced by T lymphocytes. High levels of OSM are detected in the pannus of RA patients and it may rise the inflammatory responses in joints and eventually lead to bone erosion.[65] OSM promotes angiogenesis and EC migration, and potentiates the effects of IL-1β in promoting extracellular matrix turnover and human cartilage degradation.[66] It was also demonstrated that OSM increased messenger RNA (mRNA) and protein levels of PLGF in a time- and concentration-dependent manner in RA synovial fibroblasts.