Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood–brain barrier

VC Biancardi, SJ Son, S Ahmadi, JA Filosa… - Hypertension, 2014 - Am Heart Assoc
VC Biancardi, SJ Son, S Ahmadi, JA Filosa, JE Stern
Hypertension, 2014Am Heart Assoc
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 …
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.
Am Heart Assoc