1. List the steps in the process of angiogenesis.
Angiogenesis - 
Formation of new vessels from pre-existing vessels. 

Steps in Angiogenesis (4 stages):

     Step 1: Stimulation of endothelial cells by angiogenic factors.

             Basic Fibroblast Growth Factor (bFGF) 
             1. A potent inducer of endothelial cell migration, proliferation, 
                 and tube formation. 
             2. A pleiotropic factor which is not specific for endothelial 
             3. FGF receptor is in the tyrosine kinase family.

            Vascular Endothelial Growth Factor (VEGF)
             1. Highly specific for endothelial cells. 
             2. Inducer of extracellular proteinase expression, increased 
                 expression of specific integrins for migration, and initiation 
                 of cell proliferation and migration. 
             3. Binds to endo-specific receptors Flt-1 and Flk-1 (of the 
                 tyrosine kinase family). 
             4. Expression of VEGF potentiated by hypoxia and 
                 inactivation of p53.

     Step 2: Degradation of the capillary basal lamina by 
                  activated endothelial cells (via extracellular 

            Matrix Metalloproteinases (MMPs) 
             1. A family of 22 zinc-dependent endopeptidases that degrade 
                 all extracellular matrix components. 
             2. Subgroups of collagenases, stromelysins, gelatinases, and 
                  membrane-type MMPs. 
             3. MMP1 (a collagenase), MMP2 and MT1-MMP (basal 
                 lamina degradation) are all expressed during angiogenesis.

            Urokinase (uPA) 
             1. Conversion of plasminogen (a zymogen) to plasmin (a 
                  serine rotease). 
             2. Binds cell surface receptor uPAR and get local areas of 
                 high proteolytic activity. 
             3. Binding to uPAR may induce cell prolif and regulate cell 

          Step 3: Capillary sprout formation and migration of 
                       endothelial cells.

                 Integrin Expression 
                  1. integrin proteins on newly forming vessels. 
                  2. Allow migrating endothelial cells to interact with specific 
                      components of the surrounding  matrix. 

                 Extracellular proteinases
                  1. MMps and urokinase faciliate migration of endothelium 
                      cells into surrounding matrix.

          Step 4: New Vessel Maturation

                  Angiopoeitin (Ang 1) 
                  1. Produced by the surrounding stromal cells. 
                  2. Induces endothelial cell survival and stabilization of new 
                      capillary tubes. 
                  3. Binds Tie2 receptor on endothelial cells and which 
                      inhibits apoptosis.

                 Platelet Derived Growth Factor (PDGF)
                  1. Produced by endo cells of new capi tubes. 
                  2. Recruits pericytes (that differentiate à mature) which 
                      interact with and stabilize the new vessels.

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