Healthy tissue had undamaged ECM and endothelium in the parenchyma. First developed in 1974 by Okamotoet al(Okamotoet al, 1974), SHRSP rats are a genetic model of severe hypertension with alterations in the reninangiotensin (Hilbertet al, 1991;Kimet al, 1992) and CACNA2D4 endothelin systems (Jesminet al, 2007;Savage and Jeng, 2002). These alterations contribute to the spontaneous development of cerebrovascular pathology in GNE 9605 >80% of animals, normally, around 9 weeks of age (Yamoriet al, 1976a;Yamori and Horie, 1977). Disease etiology includes cerebral lesions (ischemic or vasogenic in source), hemorrhage, and white matter rarefaction. The brain is not the only organ affected; this particular strain also develops connected kidney, heart, and lung disease (Masineniet al, 2005). Despite the plethora of studies investigating the natural GNE 9605 history of stroke in SHRSP rats, the precise mechanism(s) of disease development remain poorly recognized. Early studies concentrated within the histopathological characterization of cerebral lesions in aged animals on a normal diet, reporting presence of atherosclerotic plaque, medial degeneration, fibrinoid necrosis, hypertrophy, and thrombosis (Yamoriet al, 1976a). However, when fed a high-salt diet, disease development may be accelerated by raising peripheral resistance and increasing blood pressure (BP). This switch in diet requires advantage of the improved salt-sensitivity of the SHR and SHRSP strains, a direct result of alterations in Na+/H+exchange (Orlovet al, 2000) and Na+/K+/2Clco-transport (Sonalkeret al, 2004). Many have used this method, feeding 4- to 6-week-old GNE 9605 SHRSP rats 1.0% NaCl in drinking water, resulting in disease development 1 to 2 2 months later (Blezeret al, 1998b;Guerriniet al, 2002;Sironiet al, 2001). This means that cerebral lesions are happening as early as 3 months of age. With this method, the query occurs as to whether disease development is merely accelerated, or whether the spontaneous development of stroke on a normal diet occurs via a completely separate mechanism as when fed a high-salt diet. To day, two major mechanisms of disease development have been suggested (Number 1). The 1st (left path) may be coined progressive, in which the presence of chronic hypertension induces vascular redesigning and reduced cerebral blood flow (CBF) (Mieset al, 1999;Yamoriet al, 1976b;Yamori and Horie, 1977). Hypertrophy (medial thickening) and eutrophy (luminal narrowing) lead to improved vascular resistance and wall sheer rates. As the vessels become less functionally responsive and more extensively filled with atherosclerotic plaque, there is risk for vascular compression and thrombi. In this case, GNE 9605 ischemic lesion development occurs, followed by subacute development of cerebral edema and bloodbrain barrier (BBB) disruption. In contrast, the second (right path) occurs more quickly and is akin to hypertensive encephalopathy (Fredrikssonet al, 1985;Smedaet al, 1999;Tamakiet al, 1984). With an acute spike in BP, there is loss of CBF autoregulation and improved CBF. In this case, BBB disruption happens, followed by extravasation of serum proteins and significant vasogenic edema (Blezeret al, 1998b;Sironiet al, 2001,2004). == Number 1. == Mechanisms of lesion development in SHRSP rats. Sluggish’ development of disease happens via vascular redesigning, hypertrophy, and hypoperfusion. With this establishing, lesions develop 1st, followed by BBB disruption and formation of edema. Fast’ development of GNE 9605 disease happens via an acute spike in BP, resulting in hyperperfusion. With this setting, BBB disruption and edema happen 1st, followed by vascular compression and hypoperfusion. In this study, we used multimodal magnetic resonance imaging (MRI) with continuous arterial spin labeling (ASL) to investigate the natural history of spontaneous cerebral infarction and the specific part of cerebral perfusion in disease development in aged SHRSP rats. Histology and immunohistochemistry were performed to validate MRI findings. We hypothesize that disease development is largely ischemic, related to hypertension-induced vascular redesigning and impaired cerebral perfusion. == Materials and methods == == Animal Preparation and Monitoring == This study was authorized by the institutional animal care and use committee (IACUC) of the National.