A novel role for myeloid endothelin-B receptors in hypertension

Alicja Czopek, Rebecca Moorhouse, Léa Guyonnet, Tariq Farrah, Olivia Lenoir, Elizabeth Owen, Job van Bragt, Hannah M Costello, Filippo Menolascina, Véronique Baudrie, David J Webb, David C Kluth, Matthew A Bailey, Pierre-Louis Tharaux, Neeraj Dhaun

Research output: Contribution to journalArticlepeer-review

Abstract

Aims:
Hypertension is common. Recent data suggest that macrophages (Mφ) contribute to, and protect from, hypertension. Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor with additional pro-inflammatory properties. We investigated the role of the ET system in experimental and clinical hypertension by modifying Mφ number and phenotype.

Methods and results:
In vitro, Mφ ET receptor function was explored using pharmacological, gene silencing, and knockout approaches. Using the CD11b-DTR mouse and novel mice with myeloid cell-specific endothelin-B (ETB) receptor deficiency (LysMETB−/−), we explored the effects of modifying Mφ number and phenotype on the hypertensive effects of ET-1, angiotensin II (ANG II), a model that is ET-1 dependent, and salt. In patients with small vessel vasculitis, the impacts of Mφ depleting and non-depleting therapies on blood pressure (BP) and endothelial function were examined. Mouse and human Mφ expressed both endothelin-A and ETB receptors and displayed chemokinesis to ET-1. However, stimulation of Mφ with exogenous ET-1 did not polarize Mφ phenotype. Interestingly, both mouse and human Mφ cleared ET-1 through ETB receptor mediated, and dynamin-dependent, endocytosis. Mφ depletion resulted in an augmented chronic hypertensive response to both ET-1 and salt. LysMETB−/− mice displayed an exaggerated hypertensive response to both ET-1 and ANG II. Finally, in patients who received Mφ depleting immunotherapy BP was higher and endothelial function worse than in those receiving non-depleting therapies.

Conclusion:
Mφ and ET-1 may play an important role in BP control and potentially have a critical role as a therapeutic target in hypertension.
Original languageEnglish
Pages (from-to)768-784
Number of pages17
JournalEuropean Heart Journal
Volume40
Issue number9
Early online date17 Jan 2019
DOIs
Publication statusPublished - 1 Mar 2019

Keywords

  • Myeloid cell
  • Endothelin
  • Hypertension

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