Jason Williams, Franklyn N. Iheagwam, Sean P. Maroney, Lauren R. Schmitt, R. Dale Brown, Greta M. Krafsur, Maria G. Frid, Maxwell C. McCabe, Aneta Gandjeva, Kurt J. Williams, James P. Luyendyk, . Anthony J. Saviola, Rubin M. Tuder, Kurt Stenmark, Kirk C. Hansen
University of Colorado Denver and University of Colorado Anschutz Medical Campus. Michigan State University.
United States
American Journal of Physiology Cell Physiology
Am J Physiol Cell Physiol 2024;
DOI: 10.1152/ajpcell.00274.2024
Abstract
Pulmonary hypertension (PH) is a progressive vascular disease characterized by vascular remodeling, stiffening, and luminal obstruction, driven by dysregulated cell proliferation, inflammation, and extracellular matrix (ECM) alterations. Despite the recognized contribution of ECM dysregulation to PH pathogenesis, the precise molecular alterations in the matrisome remain poorly understood. In this study, we employed a matrisome-focused proteomics approach to map the protein composition in a young bovine calf model of acute hypoxia-induced PH. Our findings reveal distinct alterations in the matrisome along the pulmonary vascular axis, with the most prominent changes observed in the main pulmonary artery. Key alterations included a strong immune response and wound repair signature, characterized by increased levels of complement components, coagulation cascade proteins, and provisional matrix markers. Additionally, we observed upregulation of ECM-modifying enzymes, growth factors, and core ECM proteins implicated in vascular stiffening, such as collagens, periostin, tenacsin-C, and fibrin(ogen). Notably, these alterations correlated with increased mean pulmonary arterial pressure and vascular remodeling. In the plasma, we identified increased levels of complement components, indicating a systemic inflammatory response accompanying the vascular remodeling. Our findings shed light on the dynamic matrisome remodeling in early-stage PH, implicating a wound-healing trajectory with distinct patterns from the MPA to the distal vasculature. This study provides novel insights into the molecular underpinnings of PH pathogenesis and highlights potential biomarkers and therapeutic targets within the matrisome landscape.
Category
Class III. Pulmonary Hypertension Associated with Alveolar Hypoxia
Class I. Pulmonary Hypertension Associated with Inflammation
Animal Models of Pulmonary Vascular Disease and Therapy
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Pulmonary Vascular Pathology
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: No