Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability

Nitric oxide (NO) plays a critical role in vascular endothelial growth fact or (VEGF)-induced angiogenesis and vascular hyperpermeability, However, the relative contribution of different NO synthase (NOS) isoforms to these pro cesses is not known. Here, we evaluated the relative contributions of endot helial and inducible NOS (eNOS and iNOS, respectively) to angiogenesis and permeability of VEGF-induced angiogenic vessels. The contribution of eNOS w as assessed by using an eNOS-deficient mouse, and iNOS contribution was ass essed by using a selective inhibitor [L-N-6-(1-iminoethyl) lysine, L-NIL] a nd an iNOS-deficient mouse. Angiogenesis was induced by VEGF in type I coll agen gels placed in the mouse cranial window. Angiogenesis, vessel diameter , blood flow rate, and vascular permeability were proportional to NO levels measured with microelectrodes: Wild-type (WT) greater than or equal to WT with L-NIL or iNOS(-/-) > eNOS(-/-) greater than or equal to eNOS(-/-) with L-NIL. The role of NOS in VEGF-induced acute vascular permeability increas e in quiescent vessels also was determined by using eNOS- and iNOS-deficien t mice. VEGF superfusion significantly increased permeability in both WT an d iNOS-/- mice but not in eNOS(-/-) mice. These findings suggest that eNOS plays a predominant role in VEGF-induced angiogenesis and vascular permeabi lity. Thus, selective modulation of eNOS activity is a promising strategy f or altering angiogenesis and vascular permeability in vivo.