Cerebral artery remodeling in stroke‐prone spontaneously hypertensive rats

Abstract

Stroke is a major cause of disability and presents a serious and growing threat to public health [1]. Epidemiological studies have shown that stroke is the second leading cause of death in the world [2]. Among the risk factors for stroke, hypertension is the most powerful modifiable factor and the second most powerful risk factor after age [3–5]. Hypertension eventually results in target organ damage such as myocardial hypertrophy and artery remodeling [6]. Over 70% of stroke cases can be attributed to hypertension [7]. Arterial baroreflex (ABR) is one of the most important physiological mechanisms controlling blood pressure (BP) regulation. Its function, manifested as baroreflex sensitivity (BRS), correlates to the degree of end-organ damage in spontaneously hypertensive rats (SHR), a genetic model for hypertension [8]. Stroke-prone SHR (SHR-SP) is a substrain of SHR that exhibits much higher incidence of stroke compared with age-matched SHR. The mechanisms underlying such a difference remain to be fully understood. Signs of stroke, including movement of limbs, respiration, diet, fur and consciousness, were observed in 25 SHR (male 13, female 12) and 26 SHR-SP (male 13, female 13) at the age of 28 weeks. The neuroethology assessment was performed by using the Zea-Longa score (maximum score: 5, higher score indicates more severe neurological impairment). Systolic blood pressure (SBP), diastolic blood pressure (DBP) and BRS were determined in conscious rats as previously described [9]. Serial transverse paraffin sections (5 μm thick separated by 100 μm) were prepared using routine techniques. Ten slides were stained with hematoxylin-eosin and observed under light microscope. Structure of cerebral arteries with external diameter of 0.07–0.09 mm and 0.7–0.9 mm were evaluated with a SDK-2000 system for image analysis. Data are expressed as mean ± SD. Differences between the two groups were evaluated by unpaired t-test. Stroke incidence was analyzed with chi-square test. The relationships of SBP and BRS with wall thickness of cerebral arteries were assessed by univariate regression analysis. P < 0.05 was considered statistically significant. The behavior of each rat was observed separately. Positive signs occurred in 9 of the 26 SHR-SP (incidence: 34.62%), and none out of the 25 SHR (Figure 1A). The Zea-Longa score was significantly higher in SHR-SP (Figure 1B, P < 0.001 vs. SHR). SBP and DBP were significantly higher in SHR-SP (Figure 1C, P < 0.01 vs. SHR). BRS was significantly lower in SHR-SP (Figure 1D, P < 0.01 vs. SHR). Comparison of incidence of stroke, neuroethology assessment, BP and BRS between SHR and SHR-SP. 28-week-old SHR (n = 25, male 13, female 12) and SHR-SP (n = 26, male 13, female 13) were used. (A) Positive symptoms occurred in 9 of 26 SHR-SP, with a stroke incidence of 34.62%, and no animal with positive symptom was found in SHR. (B) Zea-Longa score of SHR-SP was significantly higher than that of SHR. (C) BP of SHR-SP was significant higher than that of SHR. (D) BRS of SHR-SP was significantly lower than that of SHR. **P < 0.01, ***P < 0.001 versus SHR. There was no significant difference in wall thickness, lumen diameter, wall-to-lumen ratio and wall cross sectional area between SHR-SP and SHR in the cerebral arteries with external diameter of 0.07–0.09 mm (Table 1). For cerebral arteries with external diameter of 0.7–0.9 mm, wall thickness, wall-to-lumen ratio and wall cross sectional area were significantly larger (P < 0.001), and the lumen diameter was significantly smaller (P < 0.05) in SHR-SP compared with that in SHR. In SHR-SP, the wall thickness was positively correlated with SBP (r = 0.366, P < 0.05), and negatively correlated with BRS (r = 0.596, P < 0.01). ABR dysfunction has been repeatedly reported to be present in acute stroke [10]. A recent study from this laboratory in hypertensive rats indicated that BRS is an independent predictor for stroke [9]. Results from the current study showed that hypertension and ABR dysfunction were more severe in SHR-SP than in SHR. Consistent with the relatively high BP and low BRS in SHR-SP, cerebral artery remodeling, e.g., increased vascular wall thickness and decreased lumen diameter, was also more pronounced in SHR-SP. In conclusion, cerebral artery remodeling may represent a key pathological feature that makes SHR-SP much more vulnerable to stroke than SHR.