Vascular remodelling in malignant hypertension

• Main Author: Collidge, Tara
• Published: University of Edinburgh 2006
• Subjects: 616.1
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.643335

Recently a highly controllable and reproducible animal model of MH was developed in the rat. The Inducible Hypertensive Rat (IHR) exploits conditional transgenic technology allowing renin expression to be switched on, and hypertension to develop, following exposure to a dietary inducing agent. The resulting phenotype resembles human MH, where inappropriate activation of the renin angiotensin system is also seen. This study used the IHR to characterise the development of MH with specific reference to the renal vasculature. Histological injury and hypertension were pre-dated by adventitial fibroblast proliferation and inflammatory cell infiltration. In order to determine the role of inflammatory cells the immunosuppressant FK506 was administered pre-emptively, resulting in the total abolition of hypertension and end-organ injury. To allow further investigation of inflammation, the MH phenotype was developed in mice using subcutaneous angiotensin II infusion. When MH was superimposed on a transgenic line susceptible to conditional macrophage depletion, vascular remodelling failed to occur in the mesenteric circulation where depletion was greatest. The effect of volume expansion on the IHR was assessed. Transgenic animals craved saline and the resulting fluid overload overcame cerebral autoregulation resulting in ischaemic stroke without alteration in systemic hypertension or pathology. The onset of stroke was tightly predictable and reproducible. Accordingly, the saline-loaded IHR represents a novel and inducible model of ischaemic stroke. In conclusion, this study has identified inflammation as an early and important event in the pathogenesis of MH in two rodent models. Additionally, cerebral autoregulation in the IHR could be overcome by fluid overload resulting in the dissociation of central and systemic pathology.