1. Angiogenesis in rheumatologic disorders

2. New blood vessels De novo formation Formation from pre existing vessels Endothelial formation from mesenchymal precursors Vessel formation from pre existing endothelial cells

3. Free angioblasts appear in mesoderm Angioblasts assemble into cord Differentiate into EC and form tube Primary vascular plexus

4.  Sprouting angiogenesis  intussusceptive angiogenesis

9. TNFR TNF-α (low) VEGF-2 experssion VEGFR Tie2 ANG AKt Angiogenesis TNFR TNF-α (high) caspase9 Apoptosis p p cytotoxicity

10. Inflammation Infection Other environmental stress Macrophages lymphocytes fibroblasts keratinocytes TNFR 1 TNF-α TRADD FADD RAIDD RIP caspase 8 BID tBID Cyto C APAF1 Cyto C caspase 9 caspase 2 Casp ase3, 7,6 Casp ase1 cleaves disrupts the outer mitochondrial membrane

11. TRADDTRADD TRADDTRADD RIP TRADDTRADD TRADDTRADD TRA F2 MK K3 p38MAPK MEKK 1 MEKK 7 JNK cJun cFos NIK IKKβ cdc37 NEMO Hsp90 IKKα IΚβ Κβ NF Κβ cIAP Pro- caspase3 FADD Pro- caspase8 TRADD= TNFR-associated death domain RIP= receptor interacting protein TRAF2= TNFR-associated factor 2 FADD=Fas-associated death domain cIAP=cytoplasmic inhibitor of apoptosis protein MAPK=mitogen-activated protein kinase JNK=cJun N-terminal kinase NIK=NF-κB–inducing kinase IKK=inhibitor of κB kinase p38MAPK=p38 mitogen- activated protein kinase MEKK1=mitogen-activated protein kinase/extracellular signal–related kinase kinase1 NEMO=NF-κB essential modulator MKK=MAPK kinase transcription factors induce transcription of antiapoptotic, proliferative, immunomodulatory, and inflammatory genes

12. PLCγ Sck VRAP PI3 K PIP 2 PIP 3 PIP 2 Akt/PKB BAD Caspase 9 HSP 90 eNOS NO MKK 3/6 P38 MAPKAPK2/3 HSP27 Actin reorganization Paxilin FAK SHC GR B2 SOS DAG IP3 Ras PKC Ca 2+ Raf1 MEK1/2 Erk1/2 cPLA2

13. Angiogenesis

22. Hypoxia

23. Monocytes CXC4 + lymphocytes CXC4 + CD34+ VEGFR2+ stem cells Mesenchymal stem cells Endothelium cells CXCR4 + chondrocytes Matrix metalloproteinases Differentiate into ECs V-CAM1, Occludin, FAK, ERK1/2, macrophage