The matricellular protein CCN3 supports lung endothelial homeostasis and function

Kalpana R. Betageri, Patrick A. Link, Andrew J. Haak, Giovanni Ligresti, Daniel J. Tschumperlin, Nunzia Caporarello

Research output: Contribution to journalArticlepeer-review

Abstract

Aberrant vascular remodeling contributes to the progression of many aging-associated diseases, including idiopathic pulmonary fibrosis (IPF), where heterogeneous capillary density, endothelial transcriptional alterations, and increased vascular permeability correlate with poor disease outcomes. Thus, identifying disease-driving mechanisms in the pulmonary vasculature may be a promising strategy to limit IPF progression. Here, we identified Ccn3 as an endothelial-derived factor that is upregulated in resolving but not in persistent lung fibrosis in mice, and whose function is critical for vascular homeostasis and repair. Loss and gain of function experiments were carried out to test the role of CCN3 in lung microvascular endothelial function in vitro through RNAi and the addition of recombinant human CCN3 protein, respectively. Endothelial migration, permeability, proliferation, and in vitro angiogenesis were tested in cultured human lung microvascular endothelial cells (ECs). Loss of CCN3 in lung ECs resulted in transcriptional alterations along with impaired wound-healing responses, in vitro angiogenesis, barrier integrity as well as an increased profibrotic activity through paracrine signals, whereas the addition of recombinant CCN3 augmented endothelial function. Altogether, our results demonstrate that the matricellular protein CCN3 plays an important role in lung endothelial function and could serve as a promising therapeutic target to facilitate vascular repair and promote lung fibrosis resolution.

Original languageEnglish (US)
Pages (from-to)L154-L168
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume324
Issue number2
DOIs
StatePublished - Mar 2023

Keywords

  • CCN3
  • IPF
  • lung homeostasis
  • pulmonary fibrosis
  • pulmonary vasculature

ASJC Scopus subject areas

  • Physiology (medical)
  • Physiology
  • Pulmonary and Respiratory Medicine
  • Cell Biology

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