Involvement of Bone Marrow Cells and Neuroinflammation in Hypertension

• Published in: Circulation research Vol. 117; no. 2; pp. 178 - 191
• Main Authors: Santisteban, Monica M., Ahmari, Niousha, Carvajal, Jessica Marulanda, Zingler, Michael B., Qi, Yanfei, Kim, Seungbum, Joseph, Jessica, Garcia-Pereira, Fernando, Johnson, Richard D., Shenoy, Vinayak, Raizada, Mohan K., Zubcevic, Jasenka
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 03.07.2015
• Subjects: Angiotensin II; Animals; Baroreflex - physiology; Bone Marrow Cells - physiology; Bone Marrow Transplantation; Chemokine CCL2 - biosynthesis; Chemokine CCL2 - genetics; Female; Hypertension - etiology; Hypertension - physiopathology; Hypertension - prevention & control; Interleukin-1beta - biosynthesis; Interleukin-1beta - genetics; Male; Microglia - drug effects; Microglia - physiology; Minocycline - therapeutic use; Neurogenic Inflammation - complications; Norepinephrine - blood; Paraventricular Hypothalamic Nucleus - immunology; Paraventricular Hypothalamic Nucleus - physiopathology; Radiation Chimera; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sympathetic Nervous System - drug effects; Sympathetic Nervous System - physiopathology; T-Lymphocyte Subsets - immunology; immune system; autonomic nervous system; bone marrow cells; hypertension; microglia
• ISSN: 0009-7330; 1524-4571; 1524-4571
• DOI: 10.1161/CIRCRESAHA.117.305853

RATIONALE:Microglial activation in autonomic brain regions is a hallmark of neuroinflammation in neurogenic hypertension. Despite evidence that an impaired sympathetic nerve activity supplying the bone marrow (BM) increases inflammatory cells and decreases angiogenic cells, little is known about the reciprocal impact of BM-derived inflammatory cells on neuroinflammation in hypertension. OBJECTIVE:To test the hypothesis that proinflammatory BM cells from hypertensive animals contribute to neuroinflammation and hypertension via a brain–BM interaction. METHODS AND RESULTS:After BM ablation in spontaneously hypertensive rats, and reconstitution with normotensive Wistar Kyoto rat BM, the resultant chimeric spontaneously hypertensive rats displayed significant reduction in mean arterial pressure associated with attenuation of both central and peripheral inflammation. In contrast, an elevated mean arterial pressure along with increased central and peripheral inflammation was observed in chimeric Wistar-Kyoto rats reconstituted with spontaneously hypertensive rat BM. Oral treatment with minocycline, an inhibitor of microglial activation, attenuated hypertension in both the spontaneously hypertensive rats and the chronic angiotensin II–infused rats. This was accompanied by decreased sympathetic drive and inflammation. Furthermore, in chronic angiotensin II–infused rats, minocycline prevented extravasation of BM-derived cells to the hypothalamic paraventricular nucleus, presumably via a mechanism of decreased C-C chemokine ligand 2 levels in the cerebrospinal fluid. CONCLUSIONS:The BM contributes to hypertension by increasing peripheral inflammatory cells and their extravasation into the brain. Minocycline is an effective therapy to modify neurogenic components of hypertension. These observations support the hypothesis that BM-derived cells are involved in neuroinflammation, and targeting them may be an innovative strategy for neurogenic resistant hypertension therapy.