Department of Pediatrics, MS#W140
303 E. Chicago Ave.
Chicago, IL 60611-3008 Phone: 312-503-2395
Fax: 312-503-2441
Email: s-wedgwood@northwestern.edu | Dr. Wedgwood’s research seeks to characterize the molecular mechanisms that contribute to pulmonary vascular remodeling in children with pulmonary hypertension. Several animal models have been developed to investigate the underlying causes of pulmonary hypertension and to identify potential targets for therapy.
A “Shunt” lamb model of pulmonary hypertension with increased pulmonary blood flow, developed by Dr. Jeff Fineman, displays abnormal growth factor signaling and vascular remodeling characteristic of children with congenital heart disease. Our studies suggest that biomechanical forces generated by increased pulmonary blood flow are a major contributor to the excessive pulmonary arterial muscularization evident in this model. From our data we hypothesize that biomechanical forces stimulate the generation of reactive oxygen species (ROS) in pulmonary arterial cells, which activate multiple signaling pathways resulting in increased growth factor expression and smooth muscle proliferation. In collaboration with Dr. Paul Schumacker we are currently utilizing specific intracellular probes and selective inhibitors to identify the sources of ROS in cells exposed to biomechanical forces. Additional studies include the characterization of ROS-mediated signaling pathways focusing on the transcription factors HIF-1α and E2F, and the growth factors FGF-2 and ET-1 along with their respective receptors. The effects of biomechanical forces and ROS on the expression and activity of various smooth muscle cell cycle regulatory proteins are also under investigation. These studies may provide further insight into the mechanisms of ROS-mediated cell proliferation and identify candidate target molecules for therapeutic intervention.
Dr. Robin Steinhorn utilizes a ductal ligation neonatal lamb model of pulmonary hypertension to help identify the in utero abnormalities that lead to Persistent Pulmonary Hypertension of the Newborn (PPHN). The ductal ligation model is also associated with increased ROS generation, and Dr. Steinhorn’s studies have demonstrated that antioxidants including superoxide dismutase (SOD) enhance the vasodilator response of pulmonary arteries isolated from PPHN lambs. In collaboration with Dr. Steinhorn we aim to identify the abnormal ROS-mediated pathways that increase vascular remodeling and decrease vasodilation in PPHN lambs. These studies may lead to better treatment strategies for patients with PPHN. |
