Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension
Excess macrophages and smooth muscle cells (SMCs) characterize many cardiovascular diseases, but crosstalk between these cell types is poorly defined. Pulmonary hypertension (PH) is a lethal disease in which lung arteriole SMCs proliferate and migrate, coating the normally unmuscularized distal arte...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2021-03-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.139067 |
| _version_ | 1819122263794909184 |
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| author | Aglaia Ntokou Jui M. Dave Amy C. Kauffman Maor Sauler Changwan Ryu John Hwa Erica L. Herzog Inderjit Singh W. Mark Saltzman Daniel M. Greif |
| author_facet | Aglaia Ntokou Jui M. Dave Amy C. Kauffman Maor Sauler Changwan Ryu John Hwa Erica L. Herzog Inderjit Singh W. Mark Saltzman Daniel M. Greif |
| author_sort | Aglaia Ntokou |
| collection | DOAJ |
| description | Excess macrophages and smooth muscle cells (SMCs) characterize many cardiovascular diseases, but crosstalk between these cell types is poorly defined. Pulmonary hypertension (PH) is a lethal disease in which lung arteriole SMCs proliferate and migrate, coating the normally unmuscularized distal arteriole. We hypothesized that increased macrophage platelet-derived growth factor–B (PDGF-B) induces pathological SMC burden in PH. Our results indicate that clodronate attenuates hypoxia-induced macrophage accumulation, distal muscularization, PH, and right ventricle hypertrophy (RVH). With hypoxia exposure, macrophage Pdgfb mRNA was upregulated in mice, and LysM‑Cre mice carrying floxed alleles for hypoxia-inducible factor 1a, hypoxia-inducible factor 2a, or Pdgfb had reduced macrophage Pdgfb and were protected against distal muscularization and PH. Conversely, LysM‑Cre von-Hippel Lindaufl/fl mice had increased macrophage Hifa and Pdgfb and developed distal muscularization, PH, and RVH in normoxia. Similarly, Pdgfb was upregulated in macrophages from human idiopathic or systemic sclerosis–induced pulmonary arterial hypertension patients, and macrophage-conditioned medium from these patients increased SMC proliferation and migration via PDGF-B. Finally, in mice, orotracheal administration of nanoparticles loaded with Pdgfb siRNA specifically reduced lung macrophage Pdgfb and prevented hypoxia-induced distal muscularization, PH, and RVH. Thus, macrophage-derived PDGF-B is critical for pathological SMC expansion in PH, and nanoparticle-mediated inhibition of lung macrophage PDGF-B has profound implications as an interventional strategy for PH. |
| first_indexed | 2024-12-22T06:49:41Z |
| format | Article |
| id | doaj.art-7704c153d6ae4129a8b3069803466527 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-22T06:49:41Z |
| publishDate | 2021-03-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-7704c153d6ae4129a8b30698034665272022-12-21T18:35:11ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-03-0166Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertensionAglaia NtokouJui M. DaveAmy C. KauffmanMaor SaulerChangwan RyuJohn HwaErica L. HerzogInderjit SinghW. Mark SaltzmanDaniel M. GreifExcess macrophages and smooth muscle cells (SMCs) characterize many cardiovascular diseases, but crosstalk between these cell types is poorly defined. Pulmonary hypertension (PH) is a lethal disease in which lung arteriole SMCs proliferate and migrate, coating the normally unmuscularized distal arteriole. We hypothesized that increased macrophage platelet-derived growth factor–B (PDGF-B) induces pathological SMC burden in PH. Our results indicate that clodronate attenuates hypoxia-induced macrophage accumulation, distal muscularization, PH, and right ventricle hypertrophy (RVH). With hypoxia exposure, macrophage Pdgfb mRNA was upregulated in mice, and LysM‑Cre mice carrying floxed alleles for hypoxia-inducible factor 1a, hypoxia-inducible factor 2a, or Pdgfb had reduced macrophage Pdgfb and were protected against distal muscularization and PH. Conversely, LysM‑Cre von-Hippel Lindaufl/fl mice had increased macrophage Hifa and Pdgfb and developed distal muscularization, PH, and RVH in normoxia. Similarly, Pdgfb was upregulated in macrophages from human idiopathic or systemic sclerosis–induced pulmonary arterial hypertension patients, and macrophage-conditioned medium from these patients increased SMC proliferation and migration via PDGF-B. Finally, in mice, orotracheal administration of nanoparticles loaded with Pdgfb siRNA specifically reduced lung macrophage Pdgfb and prevented hypoxia-induced distal muscularization, PH, and RVH. Thus, macrophage-derived PDGF-B is critical for pathological SMC expansion in PH, and nanoparticle-mediated inhibition of lung macrophage PDGF-B has profound implications as an interventional strategy for PH.https://doi.org/10.1172/jci.insight.139067PulmonologyVascular biology |
| spellingShingle | Aglaia Ntokou Jui M. Dave Amy C. Kauffman Maor Sauler Changwan Ryu John Hwa Erica L. Herzog Inderjit Singh W. Mark Saltzman Daniel M. Greif Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension JCI Insight Pulmonology Vascular biology |
| title | Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension |
| title_full | Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension |
| title_fullStr | Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension |
| title_full_unstemmed | Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension |
| title_short | Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension |
| title_sort | macrophage derived pdgf b induces muscularization in murine and human pulmonary hypertension |
| topic | Pulmonology Vascular biology |
| url | https://doi.org/10.1172/jci.insight.139067 |
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