SORA

Advancing, promoting and sharing knowledge of health through excellence in teaching, clinical practice and research into the prevention and treatment of illness

Vascular TSP1-CD47 signaling promotes sickle cell-associated arterial vasculopathy and pulmonary hypertension in mice

Novelli, EM; Little-Ihrig, L; Knupp, HE; Rogers, NM; Yao, M; Baust, JJ; Meijles, D; St Croix, CM; Ross, MA; Pagano, PJ; et al. Novelli, EM; Little-Ihrig, L; Knupp, HE; Rogers, NM; Yao, M; Baust, JJ; Meijles, D; St Croix, CM; Ross, MA; Pagano, PJ; DeVallance, ER; Miles, G; Potoka, KP; Isenberg, JS; Gladwin, MT (2019) Vascular TSP1-CD47 signaling promotes sickle cell-associated arterial vasculopathy and pulmonary hypertension in mice. Am J Physiol Lung Cell Mol Physiol, 316 (6). L1150-L1164. ISSN 1522-1504 https://doi.org/10.1152/ajplung.00302.2018
SGUL Authors: Meijles, Daniel Nathan

[img]
Preview
PDF Accepted Version
Available under License ["licenses_description_publisher" not defined].

Download (248kB) | Preview
[img]
Preview
PDF Accepted Version
Available under License ["licenses_description_publisher" not defined].

Download (1MB) | Preview

Abstract

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.

Item Type: Article
Additional Information: Copyright © 2019, American Journal of Physiology-Lung Cellular and Molecular Physiology
Keywords: CD47, Oxidant stress, Pulmonary hypertension, Sickle Cell Disease, Thrombospondin-1, 0606 Physiology, 1116 Medical Physiology, Respiratory System
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Am J Physiol Lung Cell Mol Physiol
ISSN: 1522-1504
Language: eng
Dates:
DateEvent
June 2019Published
20 March 2019Published Online
14 March 2019Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
1K23HL112848-01A1National Heart, Lung, and Blood Institutehttp://dx.doi.org/10.13039/100000050
2R01HL098032National Heart, Lung, and Blood Institutehttp://dx.doi.org/10.13039/100000050
1R01HL125886National Heart, Lung, and Blood Institutehttp://dx.doi.org/10.13039/100000050
5P01HL103455National Heart, Lung, and Blood Institutehttp://dx.doi.org/10.13039/100000050
T32 HL110849National Heart, Lung, and Blood Institutehttp://dx.doi.org/10.13039/100000050
PubMed ID: 30892078
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/110794
Publisher's version: https://doi.org/10.1152/ajplung.00302.2018

Actions (login required)

Edit Item Edit Item