Vascular TSP1-CD47 signaling promotes sickle cell-associated arterial vasculopathy and pulmonary hypertension in mice
| Autor: | Mark T. Gladwin, Natasha M. Rogers, Lynda Little-Ihrig, Daniel N. Meijles, Evan DeVallance, George Miles, Mingyi Yao, Mark A. Ross, Jeffrey J. Baust, Karin P. Potoka, Patrick J. Pagano, Claudette M. St. Croix, Heather E. Knupp, Jeffrey S. Isenberg, Enrico M. Novelli |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Male medicine.medical_specialty Physiology Hypertension Pulmonary Vasodilation CD47 Antigen Anemia Sickle Cell 030204 cardiovascular system & hematology Pulmonary Artery medicine.disease_cause Thrombospondin 1 03 medical and health sciences Mice 0302 clinical medicine Afterload Physiology (medical) Internal medicine medicine.artery medicine Animals Humans Receptor Cells Cultured Mice Knockout Electrical impedance myography business.industry Endothelial Cells Cell Biology medicine.disease Pulmonary hypertension Mice Inbred C57BL 030104 developmental biology Endocrinology medicine.anatomical_structure Pulmonary artery Vascular resistance Ventricular Function Right business Reactive Oxygen Species Oxidative stress Research Article |
| Zdroj: | Am J Physiol Lung Cell Mol Physiol |
| ISSN: | 1522-1504 |
| Popis: | Pulmonary hypertension (PH) is a leading cause of death in sickle cell disease (SCD) patients. Hemolysis and oxidative stress contribute to SCD-associated PH. We have reported that the protein thrombospondin-1 (TSP1) is elevated in the plasma of patients with SCD and, by interacting with its receptor CD47, limits vasodilation of distal pulmonary arteries ex vivo. We hypothesized that the TSP1-CD47 interaction may promote PH in SCD. We found that TSP1 and CD47 are upregulated in the lungs of Berkeley (BERK) sickling (Sickle) mice and patients with SCD-associated PH. We then generated chimeric animals by transplanting BERK bone marrow into C57BL/6J ( n = 24) and CD47 knockout (CD47KO, n = 27) mice. Right ventricular (RV) pressure was lower in fully engrafted Sickle-to-CD47KO than Sickle-to-C57BL/6J chimeras, as shown by the reduced maximum RV pressure ( P = 0.013) and mean pulmonary artery pressure ( P = 0.020). The afterload of the sickle-to-CD47KO chimeras was also lower, as shown by the diminished pulmonary vascular resistance ( P = 0.024) and RV effective arterial elastance ( P = 0.052). On myography, aortic segments from Sickle-to-CD47KO chimeras showed improved relaxation to acetylcholine. We hypothesized that, in SCD, TSP1-CD47 signaling promotes PH, in part, by increasing reactive oxygen species (ROS) generation. In human pulmonary artery endothelial cells, treatment with TSP1 stimulated ROS generation, which was abrogated by CD47 blockade. Explanted lungs of CD47KO chimeras had less vascular congestion and a smaller oxidative footprint. Our results show that genetic absence of CD47 ameliorates SCD-associated PH, which may be due to decreased ROS levels. Modulation of TSP1-CD47 may provide a new molecular approach to the treatment of SCD-associated PH. |
| Databáze: | OpenAIRE |
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