CCL2‐CCR2 Signalling in the Hypothalamic Paraventricular Nucleus Elicits Sympathetic‐Mediated Blood Pressure Elevations Through Monocyte and Lymphocyte Recruitment

Abstract

Chemokine C‐C motif ligand 2 (CCL2) is a chemotactic cytokine, which is elevated in the plasma of hypertensive patients. In experimental models of hypertension, CCL2 levels are increased by 3‐fold in the paraventricular nucleus of the hypothalamus (PVN). However, the underlying neural and molecular mechanisms leading to the development of hypertension still remain unknown. Here, we show for the first time that in Sprague‐Dawley rats activation of receptors for CCL2 (i.e. CCR2) in the PVN elicited biphasic blood pressure (BP) responses and changes in renal sympathetic nerve activity (RSNA), consisting of early reductions followed by long‐lasting increases in RSNA and mean arterial pressure (MAP). These responses were abolished by prior CCR2 blockade with the antagonist RS‐102895. Purinergic transmission between astrocytes and neurons mediated the initial sympathoinhibition, whereas monocyte and lymphocyte infiltration into the PVN were involved in the subsequent sympathoexcitation. Our anatomical results support these findings by showing that CCR2 are predominantly expressed in the membrane of astrocytes, which make close appositions with PVN neurons projecting to the rostral ventrolateral medulla (RVLM) ‐ where cardiovascular sympathetic premotor neurons are found. Finally, in renovascular hypertensive rats (2 kidney ‐ 1 clip) plasma and cerebrospinal fluid levels of CCL2 were elevated with an onset occurring on the first week ‐ prior to the development of hypertension. Microglia activation and lymphocyte infiltration in the PVN were also evident by the second week, when animals were still pre‐hypertensive. The results here suggest that CCL2 upregulation, microglia activation, and lymphocyte infiltration in the PVN precede the sustained increases in sympathetic activity and blood pressure observed in hypertension.Support or Funding InformationDepartment of Health, Australian Government | National Health and Medical Research Council (NHMRC): Song T Yao, GNT1079680. Rebecca L Cooper Medical Foundation: Willian S Korim. Australian Government Research Training Program Scholarships: Khalid Elsaafien. Department of Industry, Innovation, Science, Research and Tertiary Education, Australian Government | Australian Research Council (ARC): Song T Yao, FT170100363.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.