Nogo-B Receptor Modulates Pulmonary Artery Smooth Muscle Cell Function in Developing Lungs

Area of Science:

• Cardiovascular Biology
• Pulmonary Hypertension Research
• Cellular Signaling

Background:

• Nogo-B receptor (NgBR) is implicated in vascular development, but its role in pulmonary artery smooth muscle cell (PASMC) growth remains unclear.
• Pulmonary hypertension is characterized by vascular remodeling, involving PASMC proliferation and dysfunction.

Purpose of the Study:

• To investigate the role of NgBR in regulating PASMC growth and function in the context of pulmonary hypertension.
• To elucidate the mechanisms by which NgBR influences endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) formation in PASMCs.

Main Methods:

• Established a pulmonary hypertension model in fetal lambs via in utero ductus arteriosus constriction.
• Assessed PASMC protein levels, ROS formation, proliferation, and wound healing.
• Manipulated NgBR levels using small interfering RNA and plasmid DNA; induced ER stress with tunicamycin.

Main Results:

• Hypertensive fetal lamb (HTFL) PASMCs exhibited decreased NgBR levels, increased proliferation, wound healing, ER stress, and ROS formation compared to controls.
• NgBR knockdown mimicked the HTFL phenotype, while NgBR overexpression in HTFL PASMCs restored normal function.
• Decreased NgBR correlated with increased ROS, which drove PASMC proliferation and wound healing; ROS scavenging ameliorated these effects.

Conclusions:

• Reduced NgBR expression in pulmonary hypertension promotes PASMC proliferation and oxidative stress via ER stress and extracellular signal-regulated kinase pathway activation.
• This NgBR-mediated pathway contributes significantly to the pathogenesis of neonatal lung injury associated with pulmonary hypertension.