Intermittent hypoxia-induced endothelial barrier dysfunction requires ROS-dependent MAP kinase activation

Area of Science:

• Physiology
• Cell Biology
• Pathophysiology

Background:

• Endothelial barrier dysfunction is implicated in various diseases.
• Intermittent hypoxia (IH), mimicking sleep apnea, is a potential trigger for endothelial dysfunction.
• The precise molecular mechanisms underlying IH-induced endothelial barrier changes require further elucidation.

Purpose of the Study:

• To investigate the impact of simulated intermittent hypoxia (IH) on human lung microvascular endothelial cell barrier function.
• To identify the underlying molecular mechanisms, including signaling pathways and protein involvement, responsible for IH-induced endothelial barrier dysfunction.

Main Methods:

• Human lung microvascular endothelial cells were exposed to simulated IH (alternating cycles of low and normal oxygen).
• Endothelial barrier function was assessed using transendothelial electrical resistance (TEER) measurements.
• Cellular changes, protein localization (cortactin, VE-cadherin, ZO-1), kinase activation (ERK, JNK), and reactive oxygen species (ROS) levels were analyzed.

Main Results:

• IH exposure significantly decreased TEER, indicating impaired endothelial barrier function.
• IH induced stress fiber formation, altered junction protein distribution, and increased intercellular gaps.
• IH led to the phosphorylation of ERK and JNK, increased ROS production, and these effects were mitigated by kinase inhibitors and an antioxidant.

Conclusions:

• Intermittent hypoxia causes endothelial barrier dysfunction through ROS-dependent activation of MAP kinases (ERK and JNK).
• This activation leads to cytoskeletal reorganization and altered junctional protein localization, ultimately compromising endothelial barrier integrity.
• The findings highlight a critical pathway linking IH to endothelial dysfunction, relevant for conditions like sleep apnea.