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, 4, 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).
Figure 1.
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).
Table 1.
Morphological parameters of cerebral arteries in 28‐week‐old SHR and SHR‐SP
| Strain | Gender | n | W (×10−1mm) | L (×10−1mm) | W:L | WCSA (×10−2mm2) |
|---|---|---|---|---|---|---|
| external diameter 0.07–0.09 mm arteries | ||||||
| SHR | Male | 13 | 0.119 ± 0.033 | 0.572 ± 0.064 | 0.217 ± 0.052 | 0.264 ± 0.053 |
| SHR‐SP | Male | 13 | 0.118 ± 0.044 | 0.577 ± 0.094 | 0.205 ± 0.097 | 0.254 ± 0.063 |
| SHR | Female | 12 | 0.121 ± 0.082 | 0.573 ± 0.044 | 0.211 ± 0.105 | 0.256 ± 0.047 |
| SHR‐SP | Female | 13 | 0.121 ± 0.032 | 0.581 ± 0.125 | 0.208 ± 0.084 | 0.262 ± 0.085 |
| SHR | Total | 25 | 0.120 ± 0.024 | 0.572 ± 0.056 | 0.215 ± 0.059 | 0.260 ± 0.050 |
| SHR‐SP | Total | 26 | 0.120 ± 0.036 | 0.579 ± 0.092 | 0.218 ± 0.087 | 0.258 ± 0.071 |
| external diameter 0.7–0.9 mm arteries | ||||||
| SHR | Male | 13 | 0.647 ± 0.144 | 6.481 ± 0.435 | 0.100 ± 0.033 | 14.563 ± 3.145 |
| SHR‐SP | Male | 13 | 0.823 ± 0.214*** | 6.216 ± 0.537* | 0.132 ± 0.033*** | 18.102 ± 4.853*** |
| SHR | Female | 12 | 0.619 ± 0.153 | 6.477 ± 0.503 | 0.096 ± 0.040 | 14.214 ± 3.267 |
| SHR‐SP | Female | 13 | 0.804 ± 0.188*** | 6.217 ± 0.586* | 0.129 ± 0.041*** | 17.872 ± 4.824*** |
| SHR | Total | 25 | 0.638 ± 0.136 | 6.479 ± 0.462 | 0.099 ± 0.024 | 14.248 ± 3.124 |
| SHR‐SP | Total | 26 | 0.814 ± 0.190*** | 6.217 ± 0.563* | 0.133 ± 0.036*** | 17.964 ± 4.504*** |
W, wall thickness; L, lumen diameter; W:L, wall‐to‐lumen ratio; WCSA, wall cross sectional area.
*P < 0.05.
***P < 0.001 versus SHR.
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.
The first two authors contributed equally to this work.
References
- 1. Flynn RW, MacWalter RS, Doney AS. The cost of cerebral ischaemia. Neuropharmacology 2008;55:250–256. [DOI] [PubMed] [Google Scholar]
- 2. World Health Statistics 2008 . Geneva , Switzerland : World Health Organization, 2008. [Google Scholar]
- 3. Bangalore S, Messerli FH, Wun CC, et al J‐curve revisited: An analysis of blood pressure and cardiovascular events in the Treating to New Targets (TNT) Trial. Eur Heart J 2010;31:2897–2908. [DOI] [PubMed] [Google Scholar]
- 4. Bangalore S, Messerli FH, Franklin SS, Mancia G, Champion A, Pepine CJ. Pulse pressure and risk of cardiovascular outcomes in patients with hypertension and coronary artery disease: An INternational VErapamil SR‐trandolapril STudy (INVEST) analysis. Eur Heart J 2009;30:1395–1401. [DOI] [PubMed] [Google Scholar]
- 5. McAlister FA, Feldman RD, Wyard K, Brant R, Campbell NR. The impact of the Canadian Hypertension Education Programme in its first decade. Eur Heart J 2009;30:1434–1439. [DOI] [PubMed] [Google Scholar]
- 6. Chahal NS, Lim TK, Jain P, Chambers JC, Kooner JS, Senior R. New insights into the relationship of left ventricular geometry and left ventricular mass with cardiac function: A population study of hypertensive subjects. Eur Heart J 2010;31:588–594. [DOI] [PubMed] [Google Scholar]
- 7. Papadopoulos DP, Papademetriou V. Aggressive blood pressure control and stroke prevention: Role of calcium channel blockers. J Hypertens 2008;26:844–852. [DOI] [PubMed] [Google Scholar]
- 8. Shan ZZ, Dai SM, Su DF. Relationship between baroreceptor reflex function and end‐organ damage in spontaneously hypertensive rats. Am J Physiol 1999;277:H1200–H1206. [DOI] [PubMed] [Google Scholar]
- 9. Liu AJ, Ma XJ, Shen FM, Liu JG, Chen H, Su DF. Arterial baroreflex: a novel target for preventing stroke in rat hypertension. Stroke 2007;38:1916–1923. [DOI] [PubMed] [Google Scholar]
- 10. Sykora M, Diedler J, Rupp A, Turcani P, Rocco A, Steiner T. Impaired baroreflex sensitivity predicts outcome of acute intracerebral hemorrhage. Crit Care Med 2008;36:3074–3079. [DOI] [PubMed] [Google Scholar]