Sepsis-induced elevation in plasma serotonin facilitates endothelial hyperpermeability

Area of Science:

• Biomedical Science
• Cellular Biology
• Pathophysiology

Background:

• Sepsis is characterized by endothelial barrier hyperpermeability and microvascular leakage.
• Elevated plasma serotonin (5-HT) levels are observed in sepsis models.

Purpose of the Study:

• To elucidate the mechanism by which serotonin regulates microvascular permeability during sepsis.
• To investigate the role of serotonin transporter (SERT) in sepsis-induced endothelial dysfunction.

Main Methods:

• Utilized cecal ligation and puncture (CLP) model in mice.
• Examined 5-HT-induced endothelial cell permeability, including protein phosphorylation (PAK1, vimentin) and ve-cadherin association.
• Administered SERT inhibitor (paroxetine) and studied SERT knockout mice.

Main Results:

• 5-HT induced endothelial permeability via PAK1 and vimentin phosphorylation, affecting ve-cadherin.
• Inhibition of SERT with paroxetine reduced renal microvascular leakage and improved perfusion.
• SERT knockout mice exhibited significantly less microvascular dysfunction post-CLP.

Conclusions:

• Increased endothelial 5-HT uptake and signaling disrupt the endothelial barrier in sepsis.
• Regulating intracellular 5-HT levels presents a novel therapeutic strategy for sepsis-associated microvascular dysfunction.
• Findings refine understanding of 5-HT signaling in sepsis-induced endothelial barrier disruption.