Compromised blood-brain barrier permeability: novel mechanism by which circulating angiotensin II signals to sympathoexcitatory centres during hypertension

Abstract

Angiotensin II (AngII) is a pivotal peptide implicated in the regulation of blood pressure. In addition to its systemic vascular and renal effects, AngII acts centrally to modulate the activities of neuroendocrine and sympathetic neuronal networks, influencing in turn sympatho-humoral outflows to the circulation. Moreover, a large body of evidence supports AngII signalling dysregulation as a key mechanism contributing to exacerbated sympathoexcitation during hypertension. Due to its hydrophilic actions, circulating AngII does not cross the blood-brain barrier (BBB), signalling to the brain via the circumventricular organs which lack a tight BBB. In this review, we present and discuss recent studies from our laboratory showing that elevated circulating levels of AngII during hypertension result in disruption of the BBB integrity, allowing access of circulating AngII to critical sympathoexcitatory brain centres such as the paraventricular nucleus of the hypothalamus and the rostral ventrolateral medulla. We propose the novel hypothesis that AngII-driven BBB breakdown constitutes a complementary mechanism by which circulating AngII, working in tandem with the central renin-angiotensin system, further exacerbates sympatho-humoral activation during hypertension. These results are discussed within the context of a growing body of evidence in the literature supporting AngII as a pro-inflammatory signal, and brain microglia as key cell targets mediating central AngII actions during hypertension.

Figure 1. Extravasation of FITC10 within the brain in different conditions

A–D, representative images showing a comparison of extravasated (EV) FITC10 in control rats in brain areas lacking (A, subfornical organ; B, area postrema) or possessing (C, PVN; D, supraoptic hypothalamic nuclei) an intact BBB. The inset in B shows a higher magnification of the squared area. Note the presence of extravascular FITC10 in A and B, but not C or D. E–J shows increased extravasated small size FITC10 (green dye) but not large size dextran‐rhodamine 70 kDA (RHO70) (red dye), indicative of increased BBB permeability, within the PVN of spontaneous (SHR, E–G) and renovascular hypertensive rats (RVH, H–J) as indicated in the respective summary. G, summary data showing that leakage of FITC10 is blunted in SHR treated with losartan (Los) but not hydralazine (Hyd). Scale bars: 25 μm for A, C and D and inset in B; 50 μm for B, E, F, H and I. ***P < 0.001 and *P < 0.05 vs. WKY or Sham; ^††† P < 0.001 vs. SHR. n = 8 SHR/WKY in G; n = 4 SHR‐Los/SHR‐Hyd in G; n = 3 Sham/RVH in J. 3V and 4V, third and fourth ventricle; LV, lateral ventricle; VGL, ventral glial lamina; OT, optic tract (modified from Biancardi et al. 2014).

Figure 2. Circulating angiotensin II leaks into the PVN parenchyma in SHR, targeting neurons and microglia

A–C, images showing increased extravasated levels of AngII‐FITC (intravascularly delivered) within the PVN of hypertensive (SHR, B) compared with normotensive (WKY, A) rats, as indicated in the summary data (C). D and E, extravasated AngII‐FITC (green) is co‐localized with neurons (D, neuronal marker NeuN (blue) and the RHO70 dye contained in the vasculature, red) and with microglia (E, microglia marker CD11b, red). Scale bars: 50 μm. *P < 0.05 vs. WKY. n = 4 WKY/SHR. 3V: third ventricle (modified from Biancardi et al. 2014).