Smooth muscle Cxcl12 contributions to vascular remodeling in flow and hypoxia-induced pulmonary hypertension
Year: 2025
Type: article
Abstract: Patients with congenital heart disease causing significant left-to-right shunting of blood are at risk of developing pulmonary arterial hypertension (PAH). However, the underlying mechanism by which pulmonary overcirculation and shear stress drive vascular remodeling remains poorly understood. Our study established a "two-hit" murine model of severe pulmonary hypertension by combining left pneumonectomy (LP) and chronic hypoxia (LP/Hx). Using transgenic reporter lines, immunofluorescence staining, and advanced microscopy, we conducted cell-lineage tracing for vascular cells, including smooth muscle cells (SMCs), endothelial cells, and pericytes. Our findings reveal that SMCs are key contributors to the distal arteriolar remodeling following LP and LP/Hx. PCR analysis of SMCs isolated from LP/Hx animals demonstrated upregulation of markers associated with contractility, proliferation, and Cxcl12 expression. Consistently, CXCL12 was found to be overexpressed in the SMC layer of pulmonary vessels from patients with PAH-congenital heart disease. Lastly, in vitro experiments with healthy human pulmonary artery SMCs showed that laminar shear stress induces CXCL12 upregulation. These findings provide novel insights into the role of SMCs in flow-induced vascular remodeling and their mechanosensitive response to shear stress. This murine model of severe pulmonary hypertension is a valuable tool for future research and developing targeted therapeutics for patients with PAH.
Source: Journal of Biological Chemistry
Authors: Timothy Klouda, Savas T. Tsikis, Thomas I. Hirsch, Yunhye Kim, Yan Li, Julia Gaal, Zhiyue Zhao, Ingeborg Friehs, John Y.-J. Shyy, Benjamin A. Raby, Mark Puder, Ke Yuan
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,430
Funders: Poultry Hub Australia, American Heart Association, American Thoracic Society, Pulmonary Hypertension Association, Boston Children's Hospital, National Institutes of Health, Harvard Digestive Diseases Center, Harvard University, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: A novel mouse model of Pulmonary Hypertension due to systemic Endothelial Cell Dysfunction, HMS/BCH Center for Neuroscience Research, Pericyte contribution to capillary remodeling in pulmonary arterial hypertension, Integrated Training in Respiratory Research, Joint Biology Consortium Resource-based Center, Mural cells contribution to vascular remodeling in flow induced pulmonary hypertension, Integrated Epithelial and Muscosal Biology, Pericytes differentiate into smooth muscle cells through HIF2a/SDF1 activation, Research Training in Alimentary Tract Surgery
OpenAlex ID: W4410193772