IL-33/ST2 Dependent Endothelial Cell Hyperproliferation and Vascular Remodeling in Sugen/Hypoxia Mice

Pulmonary arterial hypertension (PAH) is a devastating disease that is often misdiagnosed. PAH is characterized by the remodeling of the small resistance arteries in the lungs that leads to elevated right ventricular pressure (RVP) and cardiac failure. Endothelial cells can sense danger or damage to the arterial wall caused by mechanical injury or respiratory pathogens through a subset of cytokines with an alarmin function to signal proliferation and restore barrier integrity. In this study we hypothesize that under chronic pulmonary hypertension conditions Interleukin-33 (IL-33) signals pulmonary artery endothelial cells to initiate a hyperproliferative response and this cellular event contributes to the remodeling of the vascular wall. To test this hypothesis pulmonary hypertension was induced in C57Bl/6J (wildtype), IL-33 receptor gene deleted (ST2-/-) and the upstream adaptor protein, MYD88 gene deleted (MYD88-/-) mice by exposure to 10% O2 and weekly SU5416 injections (SUHX). Arterial wall thickness increased in wild-type mice, but not ST2-/- and MYD88-/- mice, under SUHX treatments. The percentage of proliferating endothelial cells increased in wild-type mice under SUHX conditions but, this endothelial proliferative response was absent in ST2-/- and MYD88-/- mice. The C-terminal, mature form of IL-33 increased in wildtype, ST2-/- and MYD88-/- mice under SUHX conditions. This response suggests an upregulation of IL-33 and that IL-33 signaling through the ST2 receptor is important for endothelial cell proliferation and vascular remodeling in the SUHX model of pulmonary hypertension