Nitrite regulates hypoxic vasodilation via myoglobin-dependent nitric oxide generation

Area of Science:

• Physiology
• Biochemistry
• Vascular Biology

Background:

• Hypoxic vasodilation, crucial for matching blood supply to oxygen demand, has uncertain sensing and signaling mechanisms.
• Myoglobin in the heart reduces nitrite to nitric oxide (NO·) during ischemia.
• Myoglobin in fish vasculature and nitrite's role in vasodilation are recent observations.

Purpose of the Study:

• To investigate the role of endogenous nitrite and vascular myoglobin in hypoxic vasodilation.
• To elucidate the signaling pathways involved in nitrite-dependent vasodilation.

Main Methods:

• Studied nitrite-dependent hypoxic vasodilation in vivo and ex vivo.
• Utilized myoglobin knockout mice and NO synthase knockout models.
• Assessed NO· generation and soluble guanylate cyclase/cGMP signaling.

Main Results:

• Myoglobin is expressed in vascular smooth muscle and significantly contributes to nitrite-dependent hypoxic vasodilation.
• Deoxygenated myoglobin reduces nitrite to NO·, activating cGMP signaling.
• Vasodilation, NO· generation, and signaling were impaired in myoglobin-deficient mice.
• Only myoglobin, not NO synthases, was found to contribute to systemic hypoxic vasodilation.

Conclusions:

• Endogenous nitrite is a physiological mediator of hypoxic vasodilation.
• Myoglobin-driven NO· generation from nitrite enhances blood flow during hypoxia.
• This pathway is critical for matching oxygen supply to metabolic demand.