Endothelial nitric oxide synthase is downregulated during hyperdynamic sepsis

Area of Science:

• Cardiovascular Physiology
• Sepsis Pathophysiology
• Endothelial Biology

Background:

• Endothelium-derived nitric oxide (NO) release is known to decrease during endotoxic shock and polymicrobial sepsis.
• The specific cause of reduced NO release during the hyperdynamic stage of sepsis, particularly the role of endothelial NO synthase (E-NOS) downregulation, remains unclear.

Purpose of the Study:

• To investigate whether decreased release of endothelium-derived NO during the hyperdynamic stage of sepsis is due to the downregulation of endothelial NO synthase (E-NOS).

Main Methods:

• Adult rats underwent cecal ligation and puncture (CLP) to induce sepsis or a sham operation.
• Immunohistochemistry and electron microscopy were used to quantify E-NOS presence and localization in aortic endothelial cells at 10 hours post-CLP.
• Vascular responses to acetylcholine (endothelium-dependent) and nitroglycerine (endothelium-independent) were assessed in isolated aortas.

Main Results:

• The percentage of E-NOS negative endothelial cells increased significantly in septic rats (22%) compared to sham controls (7%).
• A significant reduction in E-NOS densely labeled endothelial cells (from 20% to 8%) and E-NOS positive area was observed in septic aortas.
• Vascular relaxation induced by acetylcholine was significantly impaired in septic rats, while nitroglycerine-induced relaxation remained unaffected.

Conclusions:

• Decreased expression of E-NOS in vascular endothelial cells contributes to endothelial dysfunction and reduced NO release during the early hyperdynamic stage of polymicrobial sepsis.
• The findings identify E-NOS downregulation as a key mechanism underlying endothelial cell dysfunction in early sepsis.