Modulation of eNOS activity and therapeutic uses thereof

A method of stimulating sustained production of endogenous NO in an endothelial cell, comprising exposing the endothelial cell to an effective amount of a VEGF receptor agonist that exhibits selective binding affinity for a KDR receptor and induces up-regulation of NO synthase (eNOS) in the endothelial cell, wherein the agonist comprises a VEGF variant having one or more amino acid substitutions in a loop containing FLT-1 contact residues D63, E64, and E67, wherein at least residues D63 and L66 are substituted and the binding affinity of the agonist for FLT-1 receptor is reduced as compared to the binding affinity of native VEGF for FLT-1 receptor.

A method of treating a nitric oxide (NO) associated disorder in a mammal, comprising administering to said mammal an effective amount of VEGF receptor agonist that exhibits selective binding affinity for a KDR receptor, wherein the agonist comprises a VEGF variant having two or more amino acid substitutions in a loop containing FLT-1 contact residues D63, E64, and E67, wherein at least residues D63 and L66 are substituted and the binding affinity of the agonist for FLT-1 receptor is reduced as compared to the binding affinity of native VEGF for FLT-1 receptor.