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

TLDR

Nitric oxide is essential for VEGF‑induced angiogenesis and vascular hyperpermeability, yet the specific roles of its synthase isoforms remain unclear. The study aimed to determine the relative contributions of endothelial (eNOS) and inducible (iNOS) nitric oxide synthases to VEGF‑driven angiogenesis and vascular permeability. Using eNOS‑deficient mice, iNOS‑deficient mice, and the selective inhibitor l‑NIL, the authors induced VEGF‑mediated angiogenesis in collagen gels within a cranial window and assessed acute permeability in quiescent vessels. Results showed that angiogenesis, vessel diameter, blood flow, and permeability correlated with NO levels, with eNOS‑deficient mice exhibiting markedly reduced responses, indicating eNOS predominates in VEGF‑induced angiogenesis and permeability and suggesting selective eNOS modulation as a therapeutic strategy.

Abstract

Nitric oxide (NO) plays a critical role in vascular endothelial growth factor (VEGF)-induced angiogenesis and vascular hyperpermeability. However, the relative contribution of different NO synthase (NOS) isoforms to these processes is not known. Here, we evaluated the relative contributions of endothelial and inducible NOS (eNOS and iNOS, respectively) to angiogenesis and permeability of VEGF-induced angiogenic vessels. The contribution of eNOS was assessed by using an eNOS- deficient mouse, and iNOS contribution was assessed by using a selective inhibitor [ l - N 6 -(1-iminoethyl) lysine, l -NIL] and an iNOS- deficient mouse. Angiogenesis was induced by VEGF in type I collagen 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) ≥ WT with l -NIL or iNOS −/− > eNOS −/− ≥ eNOS −/− with l -NIL. The role of NOS in VEGF-induced acute vascular permeability increase in quiescent vessels also was determined by using eNOS- and iNOS- deficient mice. VEGF superfusion significantly increased permeability in both WT and iNOS −/− mice but not in eNOS −/− mice. These findings suggest that eNOS plays a predominant role in VEGF-induced angiogenesis and vascular permeability. Thus, selective modulation of eNOS activity is a promising strategy for altering angiogenesis and vascular permeability in vivo .