Caitlin V. Lewis, Thi-Tina N. Nguyen, Timothy Porfilio, Samuel D. Burciaga, Janelle N. Posey, Mariah Jordan, Daniel Colon Hidalgo, Kurt R. Stenmark, Claudia Mickael, Christina Sul, Rebecca E. Oberley-Deegan, Cassidy Delaney, Eva S. Nozik
University of Colorado, University of Colorado Anschutz Medical Campus and Children’s Hospital Colorado. University of Nebraska Medical Center.
United States
American Journal of Phyiology Lung Cellular and Molecular Physiology
Am J Physiol Lung Cell Mol Physiol 2025;
DOI: 10.1152/ajplung.00399.2024
Abstract
Dysregulated redox signaling contributes to pulmonary hypertension (PH) and vascular depletion of the redox enzyme EC-SOD from smooth muscle cells (EC-SOD SMC KO) worsens chronic hypoxic PH. Given the important role of macrophages in PH, this study aimed to determine if interstitial macrophages (IMs) and their interactions with hyaluronan, a component of extracellular matrix (ECM), are modulated by vascular EC-SOD. Floxed wildtype (WT), EC-SOD SMC KO, and SOD mimetic- or vehicle-treated mice were exposed to hypobaric hypoxia (~10% FiO2), for 4, 14, or 21 days. Using flow cytometry, we demonstrated that the transient increase in IMs at day 4 was exacerbated in EC-SOD SMC KO mice and prevented with SOD mimetic pre-treatment. Highlighting the importance of targeting vascular oxidative stress in the early response to hypoxia, pre-treatment with a single dose of EC-SOD mimetic decreased right ventricular systolic pressure, right ventricular hypertrophy, and small vessel muscularization at day 21. To assess IM phenotypic reprogramming in hypoxia, RNAseq was performed on flow-sorted IMs revealing baseline proinflammatory activation and enhanced activation of vascular and ECM remodeling pathways in response to hypoxia in EC-SOD SMC KO IMs compared to controls. To further investigate the ECM remodeling response, we quantified IMs expressing the hyaluronan receptor Lyve1, and IM-hyaluronan binding. Lyve1+IMs and Lyve1+HA+IMs were increased in response to hypoxia in EC-SOD SMC KO mice and accumulated in the perivascular space of the lung. In conclusion, vascular EC-SOD limits IM accumulation and proinflammatory profibrotic IM signaling, including perivascular accumulation of Lyve1+IMs and their binding to hyaluronan.
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: No Age-Related Focus
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: Yes