Circulating Angiotensin II Gains Access to the Hypothalamus and Brain Stem During Hypertension via Breakdown of the Blood–Brain Barrier

Biancardi, Vinicia Campana; Son, Sook Jin; Ahmadi, Sahra; Filosa, Jessica A.; Stern, Javier E.

doi:10.1161/hypertensionaha.113.01743

Cited by 270Renin-Angiotensin System StudiesBarrier Structure and Function StudiesBlood Pressure and Hypertension Studies

Circulating Angiotensin II Gains Access to the Hypothalamus and Brain Stem During Hypertension via Breakdown of the Blood–Brain Barrier

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Biancardi, Vinicia Campana, Son, Sook Jin, Ahmadi, Sahra, Filosa, Jessica A., Stern, Javier E.·2014·Hypertension

DOI 10.1161/hypertensionaha.113.01743PMC PMC4080808

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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.

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Later studies with more moderate and long-lasting blood pressure increases or chronic hypertension found regional angiotensin II-dependent increases in blood-brain barrier permeability in some cases, but it remained unclear whether angiotensin II itself crosses the blood-brain barrier in slow pressor angiotensin II hypertension.
“Subsequent studies with more moderate and long-lasting increases in BP or in models of chronic hypertension demonstrated in some cases regional ANGII-dependent increases in BBB permeability (e.g., ref. 55), but it remained unclear whether ANGII itself was able to cross the BBB in slow pressor ANGII hypertension.”
From Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension (2016) · cites this paper as [55]

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Self-citation
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Altered Blood Brain Barrier Integrity in Hypertensive Rats: Role of Angiotensin II.
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Self-citation

Authors: Biancardi, V. C., Son, S. J., Ahmadi, S., Filosa, J. A., & Stern, J. E.
Affiliations: Augusta University (US)
ORCID: Biancardi, Vinicia Campana
Filosa, Jessica A.
Stern, Javier E.
Venue: Hypertension
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2014-03
Volume: 63
Issue: 3
Pages: 572-579
ISSN: 0194-911X (ISSN-L)
1524-4563
DOI: 10.1161/hypertensionaha.113.01743
PMC: PMC4080808
OpenAlex: W2117536760
Cited by: 270
References: 73
Citations by year: 2026: 15 · 2025: 20 · 2024: 29 · 2023: 20 · 2022: 18 · 2021: 28 · 2020: 22 · 2019: 28 · 2018: 20 · 2017: 22 · 2016: 18 · 2015: 21 · 2014: 9
FWCI: 10.89
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Hypertension (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Heart, Lung, and Blood Institute (R01HL089067, R01HL112225, HL112225)
Topics: Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
Keywords: angiotensin II, blood-brain barrier permeability, neurogenic hypertension, hypothalamus, paraventricular nucleus, nucleus tractus solitarius, rostral ventrolateral medulla, losartan, angiotensin II type 1 receptor, hydralazine, microglia, neurohumoral regulation, spontaneously hypertensive rats, neuroinflammation
MeSH terms: Angiotensin II, Animals, Blood Pressure, Blood-Brain Barrier, Brain Stem, Disease Models, Animal, Hypertension, Hypothalamus, Male, Rats, Inbred SHR, Rats, Inbred WKY, Rats, Wistar, Rats

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Circulating Angiotensin II Gains Access to the Hypothalamus and Brain Stem During Hypertension via Breakdown of the Blood–Brain Barrier

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