TSP1–CD47 signaling is upregulated in clinical pulmonary hypertension and contributes to pulmonary arterial vasculopathy and dysfunction

Rogers, Natasha M.; Sharifi‐Sanjani, Maryam; Yao, Mingyi; Ghimire, Kedar; Bienes-Martínez, Raquel; Mutchler, Stephanie; Knupp, Heather E.; Baust, Jeffrey; Novelli, Enrico M.; Ross, Mark A.; Croix, Claudette St.; Kutten, Johannes C.; Czajka, Caitlin; Sembrat, John; Rojas, Mauricio; Labrousse-Arias, David; Bachman, Timothy N.; Vanderpool, Rebecca; Zuckerbraun, Brian S.; Champion, Hunter C.; Mora, Ana L.; Straub, Adam C.; Bilonick, Richard A.; Calzada, Marı́a J.; Isenberg, Jeffrey S.

doi:10.1093/cvr/cvw218

Cited by 61 publications

(86 citation statements)

References 71 publications

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“…Prior studies have shown that TSP-1 is necessary for hypoxia-induced PH171819, but the role of TSP-1 remains unclear: as a large, multimeric protein, TSP-1 can also interact with other proteins including its receptors CD36 and CD47, which could mediate PH development20. Other studies have suggested TSP-1 may regulate NO and endothelin-1 signalling via interactions with CD47 (refs 16, 18, 21). TSP-1 can alter the vascular matrix by disrupting endothelial cell junctions and promoting migration of cells including fibroblasts and smooth muscle cells17.…”

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confidence: 99%

TGF-β activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension

et al. 2017

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Pulmonary arterial hypertension (PAH) is an obstructive disease of the precapillary pulmonary arteries. Schistosomiasis-associated PAH shares altered vascular TGF-β signalling with idiopathic, heritable and autoimmune-associated etiologies; moreover, TGF-β blockade can prevent experimental pulmonary hypertension (PH) in pre-clinical models. TGF-β is regulated at the level of activation, but how TGF-β is activated in this disease is unknown. Here we show TGF-β activation by thrombospondin-1 (TSP-1) is both required and sufficient for the development of PH in Schistosoma-exposed mice. Following Schistosoma exposure, TSP-1 levels in the lung increase, via recruitment of circulating monocytes, while TSP-1 inhibition or knockout bone marrow prevents TGF-β activation and protects against PH development. TSP-1 blockade also prevents the PH in a second model, chronic hypoxia. Lastly, the plasma concentration of TSP-1 is significantly increased in subjects with scleroderma following PAH development. Targeting TSP-1-dependent activation of TGF-β could thus be a therapeutic approach in TGF-β-dependent vascular diseases.

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confidence: 99%

TGF-β activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension

et al. 2017

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“…In these experiments, effects were reported only in vessels from female animals (182). TSP1 also inhibited NO-mediated vasodilation of pulmonary arterial rings from mice as well as rats (214), indicating that TSP1 limits vasodilation of the systemic and pulmonary vasculature. It remains to be seen whether the pulmonary arterial effects of TSP1 are secondary to increased ROS.…”

Section: B Tsp1 and Ros Signaling In Vascular And Renal Cellsmentioning

confidence: 78%

“…In a small longitudinal (n = 8) cohort, plasma TSP1 levels increased coincident with the development of scleroderma-associated PH (117). TSP1 and CD47 protein are increased in lungs and distal pulmonary arteries from PH patients compared with samples from non-PH controls (214). Bias-reduced logistic regression analysis found significant positive relationships ( p < 0.05) between parenchymal and pulmonary arterial TSP1 protein expression and PH.…”

Section: A Redox Signaling In Stem Cellsmentioning

confidence: 94%

“…Bias-reduced logistic regression analysis found significant positive relationships ( p < 0.05) between parenchymal and pulmonary arterial TSP1 protein expression and PH. Interestingly, treatment of healthy human distal pulmonary arteries with exogenous TSP1 (2.2 nM) inhibited NO-mediated vasodilation, whereas treatment with a CD47 antibody (clone B6H12) improved NO-mediated vasodilation in distal pulmonary arteries from end-stage PH lungs (214).…”

Section: A Redox Signaling In Stem Cellsmentioning

confidence: 98%

“…11). In the case of ET-1, TSP1 treatment was associated with increased vessel constriction at baseline (214). PE-stimulated vasoconstriction of aortic rings exposed in vivo to angiotensin II (Ang II) was dampened by a panel of ROS mitigators, including catalase, apocynin (a nonspecific Nox inhibitor), ML-171 (a specific Nox1 inhibitor), and Mito-TEMPO (a mitochondrial superoxide scavenger) (72).…”

Section: B Tsp1 and Ros Signaling In Vascular And Renal Cellsmentioning

confidence: 99%

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Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

Roberts

Kaur

Isenberg

2017

Antioxidants & Redox Signaling

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Significance: In contrast to structural elements of the extracellular matrix, matricellular proteins appear transiently during development and injury responses, but their sustained expression can contribute to chronic disease. Through interactions with other matrix components and specific cell surface receptors, matricellular proteins regulate multiple signaling pathways, including those mediated by reactive oxygen and nitrogen species and H 2 S. Dysregulation of matricellular proteins contributes to the pathogenesis of vascular diseases and cancer. Defining the molecular mechanisms and receptors involved is revealing new therapeutic opportunities. Recent Advances: Thrombospondin-1 (TSP1) regulates NO, H 2 S, and superoxide production and signaling in several cell types. The TSP1 receptor CD47 plays a central role in inhibition of NO signaling, but other TSP1 receptors also modulate redox signaling. The matricellular protein CCN1 engages some of the same receptors to regulate redox signaling, and ADAMTS1 regulates NO signaling in Marfan syndrome. In addition to mediating matricellular protein signaling, redox signaling is emerging as an important pathway that controls the expression of several matricellular proteins. Critical Issues: Redox signaling remains unexplored for many matricellular proteins. Their interactions with multiple cellular receptors remains an obstacle to defining signaling mechanisms, but improved transgenic models could overcome this barrier. Future Directions: Therapeutics targeting the TSP1 receptor CD47 may have beneficial effects for treating cardiovascular disease and cancer and have recently entered clinical trials. Biomarkers are needed to assess their effects on redox signaling in patients and to evaluate how these contribute to their therapeutic efficacy and potential side effects. Antioxid. Redox Signal. 27, 874-911.

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Highly Bright AIE Nanoparticles by Regulating the Substituent of Rhodanine for Precise Early Detection of Atherosclerosis and Drug Screening

et al. 2022

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Fluorescent probes capable of precise detection of atherosclerosis (AS) at an early stage and fast assessment of anti‐AS drugs in animal level are particularly valuable. Herein, a highly bright aggregation‐induced emission (AIE) nanoprobe is introduced by regulating the substituent of rhodanine for early detection of atherosclerotic plaque and screening of anti‐AS drugs in a precise, sensitive, and rapid manner. With dicyanomethylene‐substituted rhodanine as the electron‐withdrawing unit, the AIE luminogen named TPE‐T‐RCN shows the highest molar extinction coefficient, the largest photoluminescence quantum yield, and the most redshifted absorption/emission spectra simultaneously as compared to the control compounds. The nanoprobes are obtained with an amphiphilic copolymer as the matrix encapsulating TPE‐T‐RCN molecules, which are further surface functionalized with anti‐CD47 antibody for specifically binding to CD47 overexpressed in AS plaques. Such nanoprobes allow efficient recognition of AS plaques at different stages in apolipoprotein E‐deficient (apoE−/−) mice, especially for the recognition of early‐stage AS plaques prior to micro‐computed tomography (CT) and magnetic resonance imaging (MRI). These features impel to apply the nanoprobes in monitoring the therapeutic effects of anti‐AS drugs, providing a powerful tool for anti‐AS drug screening. Their potential use in targeted imaging of human carotid plaque is further demonstrated.

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TSP1–CD47 signaling is upregulated in clinical pulmonary hypertension and contributes to pulmonary arterial vasculopathy and dysfunction

Abstract: In pre-clinical models of PH CD47 targets cMyc to increase ET-1 signaling. In clinical PH TSP1-CD47 is upregulated, and in both, contributes to pulmonary arterial vasculopathy and dysfunction.

Cited by 61 publications

References 71 publications

TGF-β activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension

TGF-β activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

Highly Bright AIE Nanoparticles by Regulating the Substituent of Rhodanine for Precise Early Detection of Atherosclerosis and Drug Screening

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