title: Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood-brain barrier.
abstract: Angiotensin II-mediated vascular brain inflammation emerged as a novel pathophysiological mechanism in neurogenic hypertension. However, the precise underlying mechanisms and functional consequences in relation to blood-brain barrier (BBB) integrity and central angiotensin II actions mediating neurohumoral activation in hypertension are poorly understood. Here, we aimed to determine whether BBB permeability within critical hypothalamic and brain stem regions involved in neurohumoral regulation was altered during hypertension. Using digital imaging quantification after intravascularly injected fluorescent dyes and immunohistochemistry, we found increased BBB permeability, along with altered key BBB protein constituents, in spontaneously hypertensive rats within the hypothalamic paraventricular nucleus, the nucleus of the solitary tract, and the rostral ventrolateral medulla, all critical brain regions known to contribute to neurohumoral activation during hypertension. BBB disruption, including increased permeability and downregulation of constituent proteins, was prevented in spontaneously hypertensive rats treated with the AT1 receptor antagonist losartan, but not with hydralazine, a direct vasodilator. Importantly, we found circulating angiotensin II to extravasate into these brain regions, colocalizing with neurons and microglial cells. Taken together, our studies reveal a novel angiotensin II-mediated feed-forward mechanism during hypertension, by which circulating angiotensin II evokes increased BBB permeability, facilitating in turn its access to critical brain regions known to participate in blood pressure regulation.
authors.affiliation: Department of Physiology, Georgia Regents University, 1120 15th Street, Augusta, GA 30912. jstern@gru.edu.
authors.forename: Vinicia Campana
authors.initials: VC
authors.lastname: Biancardi
authors.forename: Sook Jin
authors.initials: SJ
authors.lastname: Son
authors.forename: Sahra
authors.initials: S
authors.lastname: Ahmadi
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Filosa
authors.forename: Javier E
authors.initials: JE
authors.lastname: Stern
mesh_terms: D000804:Angiotensin II / Q000097:blood*; D000818:Animals; D001794:Blood Pressure; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000503:physiopathology*; D001933:Brain Stem / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D007031:Hypothalamus / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017208:Rats, Wistar
chemical_list: D000804:Angiotensin II
keywords: angiotensin II; blood–brain barrier; brain stem; hypertension; hypothalamus; receptor, angiotensin, type 1