Abstract
BackgroundAngiotensin II (Ang II), a peptide hormone involved in the development of hypertension, causes systemic and cerebral inflammation, affecting brain regions important for blood pressure control. The cause-and-effect relationship between hypertension and inflammation is two-way, but the role of blood pressure in the induction of cerebral inflammation is less clear. The vulnerability of specific brain regions, particularly those important for memory, is also of interest.MethodsWe used molecular biology approaches, immunohistochemistry, and electron microscopy to examine the interdependence between the hypertensive and pro-inflammatory effects of Ang II. We examined the effect of blood pressure by administering a subpressive (200 ng/kg/min) or a pressive Ang II dose (1000 or 1900 ng/kg/min) with and without hydralazine (150 mg/L) for 1 week and used phenylephrine to increase blood pressure independently of the renin-angiotensin system.ResultsAng II increased ionized calcium-binding adaptor molecule 1 (Iba-1) levels (marker of microgliosis) in the whole brain and in the hippocampus in a dose-dependent manner. Pressive Ang II induced specific changes in microglial morphology, indicating differences in functional phenotype. An increase in hippocampal glial fibrillary acidic protein (GFAP) was seen in mice receiving pressive Ang II, while no induction of cerebral gliosis was observed after 7 days of subpressive Ang II infusion. Although phenylephrine led to increased astrogliosis, it did not affect Iba-1 expression. Pressive Ang II stimulated TNF-α production in the hippocampus, and daily treatment with hydralazine prevented this increase. Hydralazine also reduced GFAP and Iba-1 levels. With longer perfusion (14 days), subpressive Ang II led to some but not all the inflammatory changes detected with the pressive doses, mainly an increase in CD68 and Iba-1 but not of GFAP or TNF-α.ConclusionsBlood pressure and Ang II differentially contribute to hippocampal inflammation in mice. Control of blood pressure and Ang II levels should prevent or reduce brain inflammation and therefore brain dysfunctions associated with hypertension.
Highlights
Angiotensin II (Ang II), a peptide hormone involved in the development of hypertension, causes systemic and cerebral inflammation, affecting brain regions important for blood pressure control
With a different strategy to explore the effects of blood pressure, we looked at ionized calcium-binding adaptor molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) levels in the hippocampus of mice receiving the hypertensive dose of Ang II (1000 ng/kg/min) and treated with the peripheral vasodilator hydralazine (Fig. 4)
Our results show that circulating Ang II leads to hippocampal inflammation and cerebral gliosis in a dose-dependent manner and that increased blood pressure is an important contributor to the brain proinflammatory effects of Ang II in mice
Summary
Angiotensin II (Ang II), a peptide hormone involved in the development of hypertension, causes systemic and cerebral inflammation, affecting brain regions important for blood pressure control. Studies examining the role of cerebral inflammation in experimental hypertension have focused on the paraventricular nucleus (PVN), a region of the hypothalamus involved in the sympathetic control of blood pressure [15]. While finding that inflammation influenced blood pressure, they showed that hypertension, which was achieved via systemic infusion of angiotensin II (Ang II), was capable of producing increases in microglial density, soma enlargement, and reductions in microglial process length, as well as greater production of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in this brain region [16,17,18]
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