Vascular TSP1-CD47 Signaling Promotes Sickle Cell-Associated Arterial Vasculopathy and Pulmonary Hypertension in Mice.

Vascular TSP1-CD47 Signaling Promotes Sickle Cell-Associated Arterial Vasculopathy and Pulmonary Hypertension in Mice. Am J Physiol Lung Cell Mol Physiol. 2019 Mar 20;: Authors: 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 Abstract Pulmonary hypertension (PH) is a leading cause of death in sickle cell disease (SCD). Hemolysis and oxidative stress are contributing factors 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 BERK 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. Fully engrafted Sickle-to-CD47KO chimeras had lower right ventricular (RV) pressures than Sickle-to-C57BL/6J chimeras as shown by the reduced maximum pressure of the RV (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, aort...
Source: American Journal of Physiology. Lung Cellular and Molecular Physiology - Category: Cytology Authors: Tags: Am J Physiol Lung Cell Mol Physiol Source Type: research