FIRST LOOK: Signaling and Pulmonary Vascular Disease
Our laboratory has investigated the role of bone morphogenetic protein (BMP) and transforming growth factor β (TGF-β) signaling pathways in the pathogenesis of vascular disease. Loss-of-function mutations involving this pathway are implicated in several congenital vascular syndromes including heritable pulmonary arterial hypertension (HPAH) and hereditary hemorrhagic telangiectasia (HHT) syndrome. A physiologic balance of BMP, Activin, Growth Differentiating Factor (GDF) and TGF-β ligand signals are essential for coordinating vasculogenesis and angiogenesis and maintaining vascular homeostasis; similarly, an imbalance in this tightly regulated network of signals can potentiate maladaptive responses to injury and inflammation.
To discern the regulation of BMP/TGF-β signaling in vascular disease, we have employed genetic models along with small molecule and recombinant probes to modify signaling. We have found that certain members of this pathway function as mechanistic biomarkers of disease, independent of the well characterized genetic syndromes: The acquired deficiency of these ligands may serve as a penetrance factor for pulmonary vascular disease following injury, whereas administering supraphysiologic levels of ligand may rescue established pulmonary hypertension. Using primary pulmonary vascular cells obtained from patients with PAH and unaffected controls, we have interrogated vascular cell functional and transcriptional responses to shear stress and BMP/TGF-β signaling to identify cellular phenotypes that may correspond to disease phenotypes. We have utilized PET-CT molecular imaging probes to determine whether a dysregulated angiogenic phenotype may be used as a sensitive and non-invasive diagnostic tool for revealing nascent pulmonary vascular disease. Finally, we have examined the propagation of BMP/TGF-β signals in cells in real time to determine to the basis for functional specificity of distinct ligands in this signaling network.
For more information about Dr. Yu’s research, please contact Partners HealthCare Innovation by clicking here.
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