Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising/recruitment
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising/recruitment
  • Contact
Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension
Aglaia Ntokou, … , W. Mark Saltzman, Daniel M. Greif
Aglaia Ntokou, … , W. Mark Saltzman, Daniel M. Greif
Published February 16, 2021
Citation Information: JCI Insight. 2021;6(6):e139067. https://doi.org/10.1172/jci.insight.139067.
View: Text | PDF
Research Article Pulmonology Vascular biology

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

  • Text
  • PDF
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–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.

Authors

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

×

Figure 1

Lung macrophages accumulate with hypoxia and are critical for hypoxia-induced pulmonary vascular remodeling and PH.

Options: View larger image (or click on image) Download as PowerPoint
Lung macrophages accumulate with hypoxia and are critical for hypoxia-in...
WT mice were exposed to hypoxia (10% FiO2) for up to 21 days or maintained in normoxia as indicated. (A) Vibratome sections including distal arterioles of the L.L1.A1 regions of left lung were stained for markers of SMCs (α–smooth muscle actin [SMA]), macrophages (CD68), and ECs (CD31). The boxed region is shown as close-ups below. n = 6 mice. (B and C) BALF and residual lung were harvested, and single-cell suspensions were subjected to flow cytometric analysis. The percentage of total cells in the given compartment that are CD64+Ly6G– macrophages was determined. n = 3 mice per time point. (D–J) Liposomes containing PBS (vehicle) or clodronate were administered orotracheally at the onset of hypoxia (or normoxia as a control) and two times per week thereafter during the 21-day treatment. (D) Lung vibratome sections of the L.L1.A1.M1 region were stained for SMA, CD64, and CD31 with boxed regions magnified below. n = 4–5 mice. RVSP (E) and Fulton index (F; weight ratio of the right ventricle [RV] to sum of the left ventricle [LV] and septum [S]) are shown. n = 3 mice. (G and H) The percent of CD64+Ly6G– macrophages in total cells of the BALF and residual lung was determined. n = 3 mice. (I and J) Alveolar regions were stained for SMA and nuclei (DAPI), and the number of alveolar myofibroblasts (arrowheads) per 100 alveoli was determined. Arterioles are indicated by “a.” n = 3 mice. More than 500 alveoli were quantified per mouse. One-way ANOVA with Tukey’s multiple-comparison test (*, **, ***, # vs. normoxia, P < 0.05, < 0.01, < 0.001, < 0.0001, respectively) was used in B, C, and E–H, and Student’s t test was used in J. Scale bars: 25 μm.

Copyright © 2021 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts