Blood flow patterns switch VEGFR2 activity through differential S-nitrosylation and S-oxidation

Area of Science:

• Cardiovascular Biology
• Endothelial Cell Physiology
• Redox Signaling

Background:

• Vascular endothelial growth factor receptor-2 (VEGFR2) is essential for vascular homeostasis.
• Its activation and inactivation are critical for endothelial cell function.
• The role of blood flow in regulating VEGFR2 activity remained unclear.

Purpose of the Study:

• To investigate how blood flow patterns influence VEGFR2 activation and inactivation.
• To elucidate the mechanisms of flow-dependent redox regulation of VEGFR2.
• To determine the in vivo significance of VEGFR2 redox modifications in arterial endothelium.

Main Methods:

• Studied VEGFR2 cysteine modifications (oxidation and S-nitrosylation) in response to different flow conditions (laminar vs. oscillatory).
• Investigated the role of NADPH oxidase-4 and endothelial nitric oxide synthase (eNOS) in flow-induced VEGFR2 modifications.
• Utilized a mouse carotid artery partial ligation model with wild-type and C1206S mutant VEGFR2 mice to assess in vivo consequences.

Main Results:

• Oscillatory flow induces VEGFR2 oxidation at Cys1206 via NADPH oxidase-4, leading to inactivation.
• Laminar flow promotes eNOS expression and VEGFR2 S-nitrosylation at Cys1206, counteracting oxidative inactivation.
• Mice with oxidation-resistant VEGFR2 (C1206S) were protected from disturbed blood flow-induced endothelial damage and intimal hyperplasia.

Conclusions:

• Blood flow dynamically regulates VEGFR2 activity through reversible cysteine oxidation and S-nitrosylation.
• Flow-dependent redox control of VEGFR2 is a key mechanism for maintaining arterial endothelial integrity.
• Targeting VEGFR2 redox modifications may offer therapeutic strategies for vascular diseases.