Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Genetic Basis for Impaired Angiogenic Signaling in BPD


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Collapse Overview 
Collapse abstract
Bronchopulmonary dysplasia (BPD) is the chronic lung disease that follows mechanical ventilation and oxygen therapy for respiratory failure in premature newborns. Characterized by dysmorphic lung vascular growth and decreased alveolarization, BPD is a complex disease with interactions between genetic and environmental factors contributing to its pathobiology. Clinical studies strongly support a genetic basis for BPD, but genetic risk factors that contribute to the pathogenesis or severity of BPD are unknown. Over the past several years, our lab and others have implicated a critical role for impaired angiogenesis in the pathogenesis of BPD. Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and survival factor that stimulates lung angiogenesis and maintains vascular function. VEGF stimulates angiogenesis through upregulation of endothelial nitric oxide synthase (eNOS), which increases nitric oxide (NO) production. Experimental models of BPD in several species have shown that impaired VEGF signaling, decreased eNOS gene expression, and decreased NO bioavailability due to high oxidant stress increase susceptibility of the developing lung for pulmonary hypertension, impaired angiogenesis and reduced alveolarization. Clinically, reduced lung VEGF expression has been found in infants dying with BPD and pulmonary vascular disease. Inhaled NO therapy enhances alveolar and vascular growth and lowers pulmonary vascular resistance in animal models of BPD, further suggesting that reduced NO production or bioavailability may contribute to chronic lung disease in premature newborns. Additional laboratory studies have further demonstrated critical interactions between VEGF-NO signaling and other angiogenic molecules, including the angiopoietin-Tie 2 system, endothelin-1, and prostacyclin, and circulating endothelial progenitor cells (EPCs) in lung growth and structure. Based on these findings, we hypothesize that early pulmonary vascular disease contributes to the incidence and severity of BPD, and that genetic variations that impair the VEGF-NO pathways and angiogenic signaling, including circulating EPCs, increase the susceptibility of premature newborns for the development of BPD. In these studies, we will carefully characterize the clinical phenotype and subtypes of BPD through precise determination of oxygen requirement, early morbidities and serial echocardiograms. Using the quantitative phenotype, we will employ a combined population based and family based association test (involving the collection of DNA from mother, father, and affected child trios), utilizing DNA from subjects enrolled into a prospective study of premature newborns at the University of Colorado and Indiana University who are at high risk for developing BPD. Project Narrative: Bronchopulmonary dysplasia (BPD) is the chronic lung disease that follows mechanical ventilation and oxygen therapy for respiratory failure in premature newborns. Characterized by dysmorphic lung vascular growth and decreased alveolarization, BPD is a complex disease with interactions between genetic and environmental factors contributing to its pathobiology. Clinical studies strongly support a genetic basis for BPD, but genetic risk factors that contribute to the pathogenesis or severity of BPD are unknown. Over the past several years, our lab and others have implicated a critical role for impaired angiogenesis in the pathogenesis of BPD. Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and survival factor that stimulates lung angiogenesis and maintains vascular function. VEGF stimulates angiogenesis through upregulation of endothelial nitric oxide synthase (eNOS), which increases nitric oxide (NO) production. Experimental models of BPD in several species have shown that impaired VEGF signaling, decreased eNOS gene expression, and decreased NO bioavailability due to high oxidant stress increase susceptibility of the developing lung for pulmonary hypertension, impaired angiogenesis and reduced alveolarization. Clinically, reduced lung VEGF expression has been found in infants dying with BPD and pulmonary vascular disease. Inhaled NO therapy enhances alveolar and vascular growth and lowers pulmonary vascular resistance in animal models of BPD, further suggesting that reduced NO production or bioavailability may contribute to chronic lung disease in premature newborns. Additional laboratory studies have further demonstrated critical interactions between VEGF-NO signaling and other angiogenic molecules, including the angiopoietin-Tie 2 system, endothelin-1, and prostacyclin, and circulating endothelial progenitor cells (EPCs) in lung growth and structure. Based on these findings, we hypothesize that early pulmonary vascular disease contributes to the incidence and severity of BPD, and that genetic variations that impair the VEGF-NO pathways and angiogenic signaling, including circulating EPCs, increase the susceptibility of premature newborns for the development of BPD. In these studies, we will carefully characterize the clinical phenotype and subtypes of BPD through precise determination of oxygen requirement, early morbidities and serial echocardiograms. Using the quantitative phenotype, we will employ a combined population based and family based association test (involving the collection of DNA from mother, father, and affected child trios), utilizing DNA from subjects enrolled into a prospective study of premature newborns at the University of Colorado and Indiana University who are at high risk for developing BPD.
Collapse sponsor award id
R01HL085703

Collapse Time 
Collapse start date
2008-04-01
Collapse end date
2014-06-30

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