Compositions and methods for modulating vascularization

Abstract

The present invention generally provides methods for modulating formation of new blood vessels. In one embodiment, the methods include administering to a mammal an effective amount of granulocyte macrophage-colony stimulating factor (GM-CSF) sufficient to form the new blood vessels. Additionally provided are methods for preventing or reducing the severity of blood vessel damage in a mammal which methods preferably include administering to the mammal an effective amount of GM-CSF. Provided also as part of this invention are pharmaceutical products and kits for inducing formation of new blood vessels in the mammal.

1 - 48 . (canceled).  
     
     
         49 . A method for inducing new blood vessel growth in myocardial tissue of a mammal in need of such treatment comprising: 
 a) injecting an effective amount of a solution comprising a nucleic acid encoding at least one angiogenic protein or an effective fragment thereof into the myocardial tissue; and    b) administering to the mammal an effective amount of at least one of: stem cell factor (SCF), colony stimulating factor (CSF) or an effective fragment thereof, thereby inducing the new blood vessel growth in the myocardial tissue of the mammal.    
     
     
         50 . The method of  claim 49 , wherein the angiogenic factor is a vascular endothelial growth factor (VEGF) or an effective fragment thereof.  
     
     
         51 . The method of  claim 50 , wherein the VEGF is VEGF-1 or VEGF165.  
     
     
         52 . The method of  claim 49 , further comprising expressing the angiogenic protein or fragment in the myocardium.  
     
     
         53 . The method of  claim 52 , wherein the method further comprises increasing frequency of endothelial progenitor cells (EPC) in the mammal.  
     
     
         54 . The method of  claim 52 , wherein the increase in frequency of the EPC is at least about 20% as determined by a standard EPC isolation assay.  
     
     
         55 . The method of  claim 52 , wherein the method further comprises increasing EPC differentiation in the mammal.  
     
     
         56 . The method of  claim 55 , wherein the increase in EPC differentiation is at least about 20% as determined by a standard EPC culture assay or a standard hindlimb ischemia assay.  
     
     
         57 . The method of  claim 50 , wherein the level of VEGF or VEGF fragment expression is sufficient to increase neovascularization by at least about 5% as determined by a standard cornea micropocket assay.  
     
     
         58 . The method of  claim 49 , wherein the amount of administered SCF, CSF or fragment is sufficient to increase EPC bone marrow derived EPC incorporation into foci.  
     
     
         59 . The method of  claim 58 , wherein the increase in EPC bone marrow derived EPC incorporation into foci is at least about 20% as determined by a standard rodent bone marrow (BM) transplantation model.  
     
     
         60 . The method of  claim 49 , wherein the method further comprises administering at least one angiogenic protein or effective fragment thereof before or after administration of the nucleic acid to the mammal.  
     
     
         61 . The method of  claim 49 , wherein the method further comprises administering to the mammal an anti-coagulant before, during, or after administration of the nucleic acid to the mammal.  
     
     
         62 . The method of  claim 61 , wherein the anti-coagulant is one or more of urokinase, plasminogen activator, and heparin.  
     
     
         63 . The method of  claim 49 , wherein the nucleic acid is directly injected with a catheter or stent.  
     
     
         64 . The method of  claim 49 , wherein the nucleic acid is inserted into a cassette operably linked to a promoter.  
     
     
         65 . The method of  claim 49 , wherein the myocardial tissue is ischemic or is associated with infarction or dysfunction.  
     
     
         66 . The method of  claim 49 , wherein the angiogenic protein or factor is one of acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), transforming growth factor α and β (TGF-α and TFG-β), platelet-derived endothelial growth factor (PD-ECGF), platelet-derived growth factor (PDGF), tumor necrosis factor α (TNF-α), hepatocyte growth factor (HGF), insulin like growth factor (IGF), erythropoietin, colony stimulating factor (CSF), macrophage-CSF (M-CSF), granulocyte/macrophage CSF (GM-CSF), stem cell factor (SCF), angiopoetin-1 (Ang1), nitric oxidesynthase (NOS); or a mutein or fragment thereof.