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

By Dai Fukumura, T. Gohongi, A. Kadambi, Y. Izumi, J. Ang, C. Yun, D. Buerk, Paul L Huang, Rakesh K. Jain. Proceedings of the National Academy of Sciences of the United States of America, 2001

1,040 citations recorded by the source corpus.

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-N6-(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.

Subfields: Cardiology and Cardiovascular Medicine, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/12e3782f3e5ffaf92e0953ccfd0126350fa9d462

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cardiology and Cardiovascular Medicine

1. Rakesh K. Jain

In Molecular Biology

1. Rakesh K. Jain
2. Dai Fukumura
3. N. Ferrara
4. A. Adamis
5. L. Claesson‐Welsh
6. S. Kashiwagi
7. S. Koch
8. M. Shibuya

In Physiology

1. Rakesh K. Jain
2. N. Ferrara

Citations in the corpus

• The role of nitric oxide in tumour progression (2006, background): “eNOS also mediates VEGF- and angiopoietin-1 -induced angiogenesis in vivo”
• Vascular permeability, vascular hyperpermeability and angiogenesis (2008, background): “Chronic, VEGF-A/tumor mediated ++ eNOS null [79]; caveolin-1 null [88, 89]; endothelial cell-specific cav-1 TG [80]; Akt-1 null [73]; PlGF null [84]”
• Ten years of anti-vascular endothelial growth factor therapy (2016, background): “Nature Reviews | Drug Discovery 2) , binding to VEGFR2 endothelial nitric oxide synthetase (eNOS) 49 , activation of SRC and YES signalling to regulate cell-to-cell contacts 50 and activation of VE-cadherin contribute to regulation of vascular permeability 51 , more recent studies have emphasized…”
• Crosstalk of tight junction components with signaling pathways. (2008, background): “The latter induces generation of IP3 that produces an elevation in intracellular Ca that activates nitric oxide synthase (NOS) to produce NO [115–117].”
• Signal transduction by vascular endothelial growth factor receptors. (2012, background): “However, VEGF-induced permeability involves endothelial nitric oxide synthase (eNOS)mediated generation of nitric oxide (NO) (Fukumura et al. 2001). eNOS is activated either by PLCg-dependent Ca2þ influx or AKTmediated phosphorylation at S1179 of eNOS (Fig.”