Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension

Rasa Tamosiuniene, Wen Tian, Gundeep Dhillon, Lijuan Wang, Yon K. Sung, Lajos Gera, Andrew J. Patterson, Rani Agrawal, Marlene Rabinovitch, Kelly Ambler, Carlin S. Long, Norbert F. Voelkel, Mark R. Nicolls

Research output: Contribution to journalArticle

148 Scopus citations

Abstract

Rationale: Pulmonary arterial hypertension (PAH) is an incurable disease associated with viral infections and connective tissue diseases. The relationship between inflammation and disease pathogenesis in these disorders remains poorly understood. Objective: To determine whether immune dysregulation due to absent T-cell populations directly contributes to the development of PAH. Methods and Results: Vascular endothelial growth factor receptor 2 (VEGFR2) blockade induced significant pulmonary endothelial apoptosis in T-cell-deficient rats but not in immune-reconstituted (IR) rats. T cell-lymphopenia in association with VEGFR2 blockade resulted in periarteriolar inflammation with macrophages, and B cells even prior to vascular remodeling and elevated pulmonary pressures. IR prevented early inflammation and attenuated PAH development. IR with either CD8 T cells alone or with CD4-depleted spleen cells was ineffective in preventing PAH, whereas CD4-depleting immunocompetent euthymic animals increased PAH susceptibility. IR with either CD4 +CD25hi or CD4+CD25- T cell subsets prior to vascular injury attenuated the development of PAH. IR limited perivascular inflammation and endothelial apoptosis in rat lungs in association with increased FoxP3+, IL-10-and TGF-β-expressing CD4 cells, and upregulation of pulmonary bone morphogenetic protein receptor type 2 (BMPR2)-expressing cells, a receptor that activates endothelial cell survival pathways. Conclusions: PAH may arise when regulatory T-cell (Treg) activity fails to control endothelial injury. These studies suggest that regulatory T cells normally function to limit vascular injury and may protect against the development of PAH.

Original languageEnglish (US)
Pages (from-to)867-879
Number of pages13
JournalCirculation Research
Volume109
Issue number8
DOIs
StatePublished - Sep 30 2011

Keywords

  • bone morphogenetic protein receptor type 2
  • inflammation
  • pulmonary arterial hypertension
  • regulatory T cell

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Tamosiuniene, R., Tian, W., Dhillon, G., Wang, L., Sung, Y. K., Gera, L., Patterson, A. J., Agrawal, R., Rabinovitch, M., Ambler, K., Long, C. S., Voelkel, N. F., & Nicolls, M. R. (2011). Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension. Circulation Research, 109(8), 867-879. https://doi.org/10.1161/CIRCRESAHA.110.236927