Key result
Macrophage depletion and myeloid ETB receptor deficiency augmented hypertensive responses in mice, and macrophage-depleting therapy was associated with higher BP in vasculitis patients.
Why the study?
Macrophages appear to both contribute to and protect against hypertension, while endothelin-1 is a potent endogenous vasoconstrictor with pro-inflammatory properties. The role of the macrophage endothelin system in experimental and clinical hypertension required investigation.
Does macrophage depletion or myeloid-specific endothelin-B receptor deficiency affect blood pressure and endothelial function in experimental models and patients with small vessel vasculitis?
Does macrophage depletion or myeloid-specific endothelin-B receptor deficiency affect blood pressure and endothelial function in experimental models and patients with small vessel vasculitis?
Macrophages clear endothelin-1 via endothelin-B receptor-mediated endocytosis, and depleting macrophages or knocking out their ETB receptors exacerbates hypertension in both experimental models and human patients.
Answers are grounded in this paper and cite their sources.
Macrophage depletion warrants BP monitoring in vasculitis; hypothesis-generating for myeloid ETB receptor protection against hypertension.
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.
No takes yet. Share an insight, caveat, or question.
Czopek et al. (2018) studied Hypertension and small vessel vasculitis. Macrophage depletion / myeloid ETB receptor deficiency vs. Non-depleting therapies / wild-type control was evaluated on Blood pressure and endothelial function. Macrophage depletion and myeloid ETB receptor deficiency augmented hypertensive responses in mice, and macrophage-depleting therapy was associated with higher BP in vasculitis patients.
Synapse has enriched 10 related papers. Consider them for comparative context: