Hypertension-induced vascular remodeling contributes to reduced cerebral perfusion and the development of spontaneous stroke in aged SHRSP rats

Abstract

Stroke in spontaneously-hypertensive, stroke-prone (SHRSP) rats is of particular interest because the pathogenesis is believed to be similar to that in the clinical setting. In this study, we employed multi-modal MRI-ASL, DWI, T(2), GRE, T(1) (pre/post contrast)-to investigate the natural history of spontaneous cerebral infarction and the specific role of cerebral perfusion in disease development. Twelve female SHRSP rats (age: approximately 1 year) were imaged within 1 to 3 days of symptom onset. The distribution of ischemic lesions was the following: 28.1% visual, 21.9% striatal, 18.8% motorsensory, 12.5% thalamic, 12.5% auditory, 3.1% frontal/prelimbic, and 3.1% multiple areas. Ischemic lesions had significantly reduced blood flow in comparison with healthy tissue. Ischemic lesions were characterized by hyperplastic, thrombosed, and compressed vessels. These findings suggest that ischemic lesion development is related to hypertension-induced vascular remodeling and persistent hypoperfusion. This model should be useful for studying the relationship between chronic hypertension and subsequent stroke, both in terms of primary and secondary prevention.

Figure 1

Mechanisms of lesion development in SHRSP rats. ‘Slow' development of disease occurs via vascular remodeling, hypertrophy, and hypoperfusion. In this setting, lesions develop first, followed by BBB disruption and formation of edema. ‘Fast' development of disease occurs via an acute spike in BP, resulting in hyperperfusion. In this setting, BBB disruption and edema occur first, followed by vascular compression and hypoperfusion.

Figure 2

Categorical and vascular distribution of lesions in SHRSP rats. Individual lesions were distributed across frontal/prelimbic (3.1%), motorsensory (18.8%), striatal (21.9%), visual (28.1%), auditory (12.5%), and thalamic (12.5%) regions. The remaining 3.1% of lesions covered multiple categories. The most commonly affected arterial distribution was the middle cerebral artery, occurring in 50% of cases. ACA, anterior cerebral artery; MCA, middle cerebral artery; PCA, posterior cerebral artery.

Figure 3

MRI lesion distribution and characteristics in SHRSP rats. Lesions appeared hyperintense (arrows) on T₂ and hypointense on ASL (red outline) in contrast to healthy tissue. Lesions had significantly reduced CBF values when compared with those in healthy tissue. Lesions coincident with BBB disruption appeared hyperintense (arrows) on T_1diff. Lesions with an intact BBB showed no evidence of enhancement (asterisks).

Figure 4

Histopathological evaluation of vascular remodeling. Hematoxylin–eosin (left) and EB (right) provide evidence of hypertension-induced vascular remodeling present in aged SHRSP rats with spontaneous stroke. In MRI-confirmed stroke regions, vessels were clotted (asterisks), compressed (arrows), and hypertrophied (asterisks). Regions with BBB disruption on MRI were well-correlated with the extravasation of EB. Scale bar=100 μm (top images, × 20) and 50 μm (bottom images, × 40).

Figure 5

Immunofluorescence of BBB disruption. Laminin and Reca-1 double immunofluorescence was performed for assessment of the extracellular matrix (laminin, green) and endothelium (Reca-1, red). Healthy tissue had intact ECM and endothelium in the parenchyma. These areas were T_1diff-negative. The affected regions showed loss of laminin staining and/or loss of Reca-1 staining. Images = × 40. Those with loss of both laminin and Reca-1 staining were T_1diff-positive.