Quinn A. Bonafiglia, Yu-Qing Zhou, Guangpei Hou, Rhidita Saha, Ying-Han R. Hsu, Jonah Burke-Kleinman, Michelle P. Bendeck
University of Toronto, Ted Rogers Centre for Heart Research and University Health Network.
Canada
American Journal of Respiratory Cell and Molecular Biology
Am J Respir Cell Mol Biol 2022; 67: 562-573
DOI: 10.1165/rcmb.2022-0124OC
Abstract
Pulmonary hypertension (PH) is a multifaceted condition characterized by elevated pulmonary arterial pressure, which can result in right ventricular dysfunction and failure. Disorders of lung development can present with secondary PH, which is a leading cause of mortality in infants with bronchopulmonary dysplasia (BPD). DDR1 (discoidin domain receptor 1) is a collagen-binding receptor that regulates tissue fibrosis and inflammation and controls cellular growth and migration. However, the roles of DDR1 in lung development or the pathogenesis of PH are unknown. Studying mice with a DDR1 deletion (Ddr1-/-), we have noted 35% mortality between 1 and 4 months of age, and we demonstrate that DDR1 deficiency results in reduced right ventricular contractility and muscularization of distal pulmonary arteries, consistent with PH. Pathology analysis revealed enlarged alveolar spaces in Ddr1-/- mice by Postnatal Day 7, consistent with impaired alveolar development. Gene expression analysis showed that Ddr1-/- mice have reduced concentrations of alveologenesis factors and epithelial-to-mesenchymal transition markers. Mechanistic studies in vitro confirmed that DDR1 mediated epithelial-to-mesenchymal transition, migration, and growth of alveolar epithelial cells. Taken together, these data suggest that DDR1 plays important roles mediating alveolarization during lung development. Our studies also describe a new model of spontaneous PH and bronchopulmonary dysplasia in mice.
Category
Class III. Pulmonary Hypertension Associated with Lung Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Filed (PHiled). Greater than 1-2 years since publication
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