The role of the renin–angiotensin system in malignant vascular injury affecting the systemic and cerebral circulations

Abstract

Malignant hypertension is a rare but serious syndrome complicating 1% of essential hypertension and causing neurological, renal and cardiac complications. Despite improved anti-hypertensive medication, the incidence of this condition fails to decline. In the first part of this review, we discuss transgenic rat models of malignant hypertension, generated by over-expressing renin, to illustrate the role of the renin-angiotensin system in the development of systemic hypertensive vascular remodelling and hypertension. In the second part, we focus on the cerebrovascular response to hypertension and discuss new data using a conditional, transgenic model of malignant hypertension, the inducible hypertensive rat (IHR). Cerebral infarction associates strongly with hypertension in man and the mechanisms by which hypertension predisposes to different types of stroke remains poorly understood. Rats have similar cerebrovascular anatomy and structure to humans and as such provide a good experimental tool. To date, such models lack controllability and blood-pressure matched controls. Using the IHR, we have manipulated dietary salt and water intake to generate a novel, controllable stroke phenotype. Hypertensive small-vessel stroke develops over a predictable time period, permitting the study of developing cerebrovascular lesions. Systemic end-organ injury and hypertension are not affected. Dissociation of the systemic and central vascular responses in this way, will allow for comparative study of animals with equivalent hypertension, genetic background and systemic features of hypertension with or without stroke.

Doin vivoExperimental Models Reflect Human Cerebral Small Vessel Disease? a Systematic Review

“…(Yamori et al, 1976;Ogata et al, 1981;Fredriksson et al, 1985;Kawashima et al, 2003;Sironi et al, 2004b), distributed in cortex and striatum, usually with a haemorrhagic component. Similar lesions were seen in R + A + transgenic mice (Baumbach et al, 2003;Iida et al, 2005;Wakisaka et al, 2008), possibly also in IHRs (Collidge et al, 2004). The focal infarcts in long-term hypertensive monkeys were histologically different, very small and non-cavitated (Kemper et al, 1999(Kemper et al, , 2001.…”

“…Vessel wall changes were observed in peripheral tissues-kidney, heart, and mesentery-with medial thickening and fibrinoid necrosis at 14 days, but no brain histopathology (Kantachuvesiri et al, 2001). To generate stroke lesions, adult rats in which the transgene had been induced were offered 0.9% saline in addition to drinking water (Collidge et al, 2004). Multiple small haemorrhagic lesions were reported (Collidge et al, 2004).…”

“…Multiple small haemorrhagic lesions were reported (Collidge et al, 2004). By 14 days after induction, saline-offered IHR were in poor condition, with some mortality, and fluid intake risen to B200 mL per day (Collidge et al, 2004). R + /A + mice are double transgenic for human renin and human angiotensinogen (Baumbach et al, 2003;Iida et al, 2005;Wakisaka et al, 2008).…”

Models That Matter: White Matter Stroke Models

“…Rats transgenic for an inducible variant of the mouse renin gene (under the control of the cytochrome P450 promoter) develop systemic hypertension and related organ effects within roughly 2 weeks of transgene induction [51,52]. Interestingly, no brain pathology was noted at 14 days.…”

“…This was associated with increasing mortality [52]. Mice transgenic for human renin and human angiotensinogen require a "second hit" for the development of significant systemic hypertension and CNS pathology [53,54].…”