Artery- and vein-specific proteins and uses therefor

Abstract

Arterial and venous endothelial cells are molecularly distinct from the earliest stages of angiogenesis. This distinction is revealed by expression on arterial cells of a transmembrane ligand, called EphrinB2 whose receptor EphB4 is expressed on venous cells. Targeted disruption of the EphrinB2 gene prevents the remodeling of veins from a capillary plexus into properly branched structures. Moreover, it also disrupts the remodeling of arteries, suggesting that reciprocal interactions between pre-specified arterial and venous endothelial cells are necessary for angiogenesis. This distinction can be used to advantage in methods to alter angiogenesis, methods to assess the effect of drugs on artery cells and vein cells, and methods to identify and isolate artery cells and vein cells, for example.

1 - 15 . (canceled) 
     
     
         16 . A method for selectively delivering an agent to veins in a mammal, comprising administering to the mammal a complex comprising:
 (a) the agent, and   (b) a component which binds EphB4, under conditions appropriate for the component of (b) to bind EphB4, whereby the agent is delivered to veins.   
     
     
         17 - 22 . (canceled) 
     
     
         23 . A transgenic nonhuman mammal having an indicator gene which is detectably expressed in cells of arteries but not cells of veins. 
     
     
         24 . The transgenic nonhuman mammal of  claim 23  wherein the indicator gene is inserted in an artery-specific Ephrin family ligand gene. 
     
     
         25 - 28 . (canceled) 
     
     
         29 . A transgenic nonhuman mammal having an indicator gene which is expressed in venous endothelial cells but not in arterial endothelial cells. 
     
     
         30 . The transgenic nonhuman mammal of  claim 29  wherein the indicator gene is inserted in a vein-specific Eph family receptor gene. 
     
     
         31 . The transgenic nonhuman mammal of  claim 30  wherein the vein-specific Eph family receptor gene encodes EphB4. 
     
     
         32 - 76 . (canceled) 
     
     
         77 . The transgenic nonhuman mammal of  claim 24  wherein the artery-specific Ephrin family ligand gene encodes EphrinB2. 
     
     
         78 . A method for testing an effect of a drug on growth of arteries, comprising administering the drug to a transgenic nonhuman mammal of  claim 23 , observing the effect of the drug on the growth of arteries, and comparing the effect to that produced in a suitable control mammal. 
     
     
         79 . A method for testing an effect of a drug on growth of veins, comprising administering the drug to a nonhuman mammal of  claim 29 , observing the effect of the drug on the growth of veins, and comparing the effect to that produced in a suitable control mammal. 
     
     
         80 . The transgenic nonhuman mammal of  claim 23  wherein the mammal is a mouse. 
     
     
         81 . The transgenic nonhuman mammal of  claim 29  wherein the mammal is a mouse. 
     
     
         82 . An article of manufacture, comprising: a container; a label; and a composition comprising an Eph receptor antagonist contained within the container; wherein the label indicates that the composition can be used to treat a disease or disorder characterized by undesirable or excessive vascularization or vascular permeability. 
     
     
         83 . The article of manufacture of  claim 82  further comprising instructions for administering the Eph receptor antagonist to a mammal to treat a disease or disorder in the mammal. 
     
     
         84 . An article of manufacture, comprising: a container; a label; and a composition comprising an Eph receptor agonist contained within the container; wherein the label indicates that the composition can be used to stimulate angiogenesis. 
     
     
         85 . The article of manufacture of  claim 84  further comprising instructions for administering the Eph receptor agonist to a mammal to treat a disease or disorder in the mammal. 
     
     
         86 . The method of  claim 16 , wherein the agent is a diagnostic agent. 
     
     
         87 . The method of  claim 16 , wherein the agent is an imaging agent. 
     
     
         88 . The method of  claim 16 , wherein the agent is a drug. 
     
     
         89 . The method of  claim 86 , wherein the diagnostic agent comprises a label selected from the group consisting of a radioactive label, a fluorescent label, a calorimetric label, an enzyme label, an antigenic label, an epitopic label and a biotin label.