NOTCH3 SIGNALING IS REQUIRED FOR THE DEVELOPMENT OF PULMONARY ARTERIAL HYPERTENSION

Notch receptor signaling is implicated in controlling smooth muscle cell proliferation and maintaining smooth muscle cells in an undifferentiated state. Pulmonary arterial hypertension is a disease characterized by excessive vascular smooth muscle cell proliferation in small pulmonary arteries, leading to elevation of pulmonary vascular resistance with consequent right ventricular failure and death. Here we show that human pulmonary hypertension is characterized by overexpression of NOTCH3 in small pulmonary artery smooth muscle cells, and that severity of disease in humans and rodents correlates with the amount of Notch3 protein in the lung. We further demonstrate that mice with homozygous deletion of Notch3 do not develop pulmonary hypertension in response to hypoxic stimulation. We report that pulmonary hypertension can be successfully treated in rodents by administration of DAPT, a γ-secretase inhibitor that blocks activation of Notch3 in smooth muscle cells. We demonstrate a mechanistic link between NOTCH3 receptor signaling through HES5 and smooth muscle cell proliferation and a shift to an undifferentiated smooth muscle cell phenotype. These data suggest that the NOTCH3-HES5 signaling pathway is crucial for the development of pulmonary arterial hypertension and provides a target pathway for therapeutic intervention.