Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension

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

doi:10.1172/jci.insight.139067

Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension

Aglaia Ntokou,¹ Jui M. Dave,¹ Amy C. Kauffman,² Maor Sauler,¹ Changwan Ryu,¹ John Hwa,¹ Erica L. Herzog,¹ Inderjit Singh,¹ W. Mark Saltzman,² and Daniel M. Greif¹

Published February 16, 2021 - More info

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Abstract

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 (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 is upregulated in mice, and LysM Cre mice carrying floxed alleles for hypoxia-inducible factor 1a, 2a, or Pdgfb have reduced macrophage Pdgfb and are protected against distal muscularization and PH. Conversely, LysM Cre, von-Hippel Lindau^(flox/flox) mice have increased macrophage Hifa and Pdgfb and develop distal muscularization, PH and RVH in normoxia. Similarly, Pdgfb is upregulated in macrophages from human idiopathic or systemic sclerosis-induced pulmonary arterial hypertension patients, and macrophage-conditioned medium from these patients increases SMC proliferation and migration via PDGF-B. Finally, in mice, orotracheal administration of nanoparticles loaded with Pdgfb siRNA specifically reduces lung macrophage Pdgfb and prevents 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.

Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension

Aglaia Ntokou,¹ Jui M. Dave,¹ Amy C. Kauffman,² Maor Sauler,¹ Changwan Ryu,¹ John Hwa,¹ Erica L. Herzog,¹ Inderjit Singh,¹ W. Mark Saltzman,² and Daniel M. Greif¹

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Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension

Aglaia Ntokou,1 Jui M. Dave,1 Amy C. Kauffman,2 Maor Sauler,1 Changwan Ryu,1 John Hwa,1 Erica L. Herzog,1 Inderjit Singh,1 W. Mark Saltzman,2 and Daniel M. Greif1

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Aglaia Ntokou,¹ Jui M. Dave,¹ Amy C. Kauffman,² Maor Sauler,¹ Changwan Ryu,¹ John Hwa,¹ Erica L. Herzog,¹ Inderjit Singh,¹ W. Mark Saltzman,² and Daniel M. Greif¹