title: Brain-derived neurotrophic factor modulates angiotensin signaling in the hypothalamus to increase blood pressure in rats.
abstract: Brain-derived neurotrophic factor (BDNF) expression increases in the paraventricular nucleus of the hypothalamus (PVN) in response to hypertensive stimuli including stress and hyperosmolarity. However, it is unclear whether BDNF in the PVN contributes to increases in blood pressure (BP). We tested the hypothesis that increased BDNF levels within the PVN would elevate baseline BP and heart rate (HR) and cardiovascular stress responses by altering central angiotensin signaling. BP was recorded using radiotelemetry in male Sprague-Dawley rats after bilateral PVN injections of adeno-associated viral vectors expressing green fluorescent protein (GFP) or myc epitope-tagged BDNF fusion protein. Cardiovascular responses to acute stress were evaluated 3 to 4 wk after injections. Additional GFP and BDNF-treated animals were equipped with osmotic pumps for intracerebroventricular infusion of saline or the angiotensin type-1 receptor (AT1R) inhibitor losartan (15 μg·0.5 μl(-1)·h(-1)). BDNF treatment significantly increased baseline BP (121 ± 3 mmHg vs. 99 ± 2 mmHg in GFP), HR (394 ± 9 beats/min vs. 314 ± 4 beats/min in GFP), and sympathetic tone indicated by HR- and BP-variability analysis and adrenomedullary tyrosine hydroxylase protein expression. In contrast, body weight and BP elevations to acute stressors decreased. BDNF upregulated AT1R mRNA by ∼80% and downregulated Mas receptor mRNA by ∼50% in the PVN, and losartan infusion partially inhibited weight loss and increases in BP and HR in BDNF-treated animals without any effect in GFP rats. Our results demonstrate that BDNF overexpression in the PVN results in sympathoexcitation, BP and HR elevations, and weight loss that are mediated, at least in part, by modulating angiotensin signaling in the PVN.
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida; Department of Pharmacology, University of Vermont College of Medicine, Burlington, Vermont; and berdos@uvm.edu.
authors.forename: Benedek
authors.identifier: http://orcid.org/0000-0002-9074-2491
authors.initials: B
authors.lastname: Erdos
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida;
authors.forename: Iara
authors.initials: I
authors.lastname: Backes
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida;
authors.forename: Michael L
authors.initials: ML
authors.lastname: McCowan
authors.affiliation: Department of Physiological Sciences, University of Florida, Gainesville, Florida.
authors.forename: Linda F
authors.initials: LF
authors.lastname: Hayward
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida;
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Scheuer
mesh_terms: D000313:Adrenal Medulla / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage; D000809:Angiotensins / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics; D002319:Cardiovascular System / Q000294:innervation*; D000229:Dependovirus / Q000235:genetics; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006339:Heart Rate; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D057967:Infusions, Intraventricular; D008297:Male; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013315:Stress, Psychological / Q000378:metabolism / Q000503:physiopathology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000809:Angiotensins; D019208:Brain-Derived Neurotrophic Factor; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D014446:Tyrosine 3-Monooxygenase
keywords: angiotensin; blood pressure; body weight; brain-derived neurotrophic factor; stress