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BMPRII influences the response of pulmonary microvascular endothelial cells to inflammatory mediators

  • Molecular and cellular mechanisms of disease
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Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Mutations in the bone morphogenetic protein receptor (BMPR2) gene have been observed in 70 % of patients with heritable pulmonary arterial hypertension (HPAH) and in 11–40 % with idiopathic PAH (IPAH). However, carriers of a BMPR2 mutation have only 20 % risk of developing PAH. Since inflammatory mediators are increased and predict survival in PAH, they could act as a second hit inducing the development of pulmonary hypertension in BMPR2 mutation carriers. Our specific aim was to determine whether inflammatory mediators could contribute to pulmonary vascular cell dysfunction in PAH patients with and without a BMPR2 mutation. Pulmonary microvascular endothelial cells (PMEC) and arterial smooth muscle cells (PASMC) were isolated from lung parenchyma of transplanted PAH patients, carriers of a BMPR2 mutation or not, and from lobectomy patients or lung donors. The effects of CRP and TNFα on mitogenic activity, adhesiveness capacity, and expression of adhesion molecules were investigated in PMECs and PASMCs. PMECs from BMPR2 mutation carriers induced an increase in PASMC mitogenic activity; moreover, endothelin-1 secretion by PMECs from carriers was higher than by PMECs from non-carriers. Recruitment of monocytes by PMECs isolated from carriers was higher compared to PMECs from non-carriers and from controls, with an elevated ICAM-1 expression. CRP increased adhesion of monocytes to PMECs in carriers and non-carriers, and TNFα only in carriers. PMEC from BMPR2 mutation carriers have enhanced adhesiveness for monocytes in response to inflammatory mediators, suggesting that BMPR2 mutation could generate susceptibility to an inflammatory insult in PAH.

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Acknowledgments

MD is holder of the Actelion chair for Pulmonary Hypertension at the University of Leuven. The authors would like to thank Jennifer Arthur-Ataam for her help in isolating pulmonary vascular cells.

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Authors and Affiliations

  1. Respiratory Division, Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium

    Leanda Vengethasamy, Birger Tielemans & Stijn Verleden

  2. UMR-S 999, INSERM and Université Paris–Sud, Laboratoire d’Excellence (LabEx) en Recherche sur le Médicament et l’Innovation Thérapeutique (LERMIT), Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France

    Aurélie Hautefort & Frédéric Perros

  3. Respiratory Division, University Hospitals and Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium

    Catharina Belge, Marion Delcroix & Rozenn Quarck

  4. Service de Chirurgie Thoracique, Vasculaire et de Transplantation Cardio-Pulmonaire, Laboratoire de Recherche Chirurgicale, INSERM U999, Centre Chirurgical Marie Lannelongue, Université Paris–Sud, Le Plessis-Robinson, France

    Elie Fadel

  5. Experimental Thoracic Surgery and Thoracic Surgery Unit, University Hospitals, University of Leuven, Leuven, Belgium

    Dirk Van Raemdonck

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  1. Leanda Vengethasamy
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Correspondence to Rozenn Quarck.

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Vengethasamy, L., Hautefort, A., Tielemans, B. et al. BMPRII influences the response of pulmonary microvascular endothelial cells to inflammatory mediators. Pflugers Arch - Eur J Physiol 468, 1969–1983 (2016). https://doi.org/10.1007/s00424-016-1899-1

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  • DOI: https://doi.org/10.1007/s00424-016-1899-1

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