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(Stroke. 1996;27:1118-1123.)
© 1996 American Heart Association, Inc.

Articles

Confocal Microscopic Characterization of a Lesion in a Cerebral Vessel of the Stroke-Prone Spontaneously Hypertensive Rat

Silvia M. Arribas, PhD; John F. Gordon, PhD; Craig J. Daly, MSc; Anna F. Dominiczak, MD John C. McGrath, PhD

From the Clinical Research Initiative in Heart Failure, Institute of Biomedical and Life Sciences, and the Department of Medicine and Therapeutics (A.F.D.), Western Infirmary, University of Glasgow (UK).

Correspondence to Dr S.M. Arribas, Clinical Research Initiative in Heart Failure, Institute of Biomedical and Life Sciences, West Medical Bldg, University of Glasgow, Glasgow G12 8QQ, UK. E-mail s.arribas@biomed.gla.ac.uk.

	Abstract

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Background and Purpose Hypertension is a major risk factor for stroke and is associated with alterations in vascular structure and function. The aim of this study was to determine vascular function, wall morphology, and vascular smooth muscle cell (VSMC) arrangement in basilar arteries from stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive control strain Wistar-Kyoto rats (WKY). The effect of perindopril treatment on SHRSP structure and function was also assessed.

Methods VSMC orientation was determined with laser-scanning confocal microscopy and computer-assisted image processing in basilar arteries stained with 5(6)-carboxyfluorescein (wavelengths: excitation, 488; emission, 515) or propidium iodide (excitation, 529; emission, 550). Measurements of wall morphology and functional responses to serotonin and KCl were assessed with wire myography.

Results In the WKY basilar arteries, VSMCs were uniformly oriented perpendicular to the longitudinal axis of the vessel, whereas in the SHRSP there were localized foci of VSMC geometric disorganization, with a significant deviation from 90°. The SHRSP basilar arteries also showed structural remodeling and reduced contractile responses to serotonin and KCl. Perindopril treatment normalized blood pressure, prevented wall morphology alterations, and improved function but had no effect on VSMC disorganization.

Conclusions This is the first demonstration of lesions of VSMC geometric disorganization in a cerebral artery from a stroke-prone genetically hypertensive rat strain. These structural abnormalities are independent of blood pressure. Their functional sequel may play a role in the pathogenesis of stroke in this model.

Key Words: basilar artery • computer-assisted image processing • hypertension • muscle, smooth • rats

	Introduction

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Hypertension is a major risk factor for stroke^{1 2} and silent cerebral infarction in humans.³ The SHRSP⁴ is a model of genetic hypertension with high incidence of stroke and is regarded as a good pathogenic model for study of stroke in humans.⁵

Established hypertension is associated with alterations in vascular structure that are due to vascular hypertrophy or eutrophic remodeling. This phenomenon is conventionally described in terms of the average overall dimensions of the vessel wall^{6 7} but not by the detailed arrangement of the cells. LSCM provides a new tool to identify in situ cells in small vessels. Either nuclear or extracellular fluorescent dyes have been shown to identify with good resolution the VSMC location and orientation in resistance arteries.⁸ The aims of the present study were to determine in isolated basilar arteries from SHRSP and their normotensive reference strain WKY (1) the VSMC geometric arrangement in situ, (2) the vascular morphology, and (3) the responses to agonists. The effects of antihypertensive treatment with the angiotensin-converting enzyme inhibitor perindopril on VSMC geometric arrangement, vascular morphology, and function were also examined.

	Materials and Methods

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Animals
SHRSP and WKY were obtained from the Glasgow colony, which has been inbred in the Department of Medicine and Therapeutics, University of Glasgow, since 1991.⁹ Thirty-six SHRSP and 36 WKY were used. One pair, matched for sex and age, was killed by inhalation of halothane 3% to 4% in oxygen for each experiment. An additional group of 6 control SHRSP and 6 SHRSP-P (SHRSP treated with perindopril, 2 mg/kg per day, from week 8 to week 16 of age) was also used. The experiments were approved by the home office according to regulations regarding experiments in animals in the United Kingdom.

Drugs and Solutions
All experiments were performed with PSS consisting of (mmol/L) NaCl 118.4, KCl 4.7, CaCl₂ 2.5, KH₂PO₄ 1.2, MgSO₄ 1.2, NaHCO₃ 25, glucose 11.1, and Na₂EDTA 0.023. The solution was bubbled with 95% O₂–5% CO₂ to give a pH of 7.4 at 37°C. The 125-mmol/L KCl solution was prepared by substitution of 125 mmol/L KCl for NaCl in PSS. Drugs used were 5(6)-carboxyfluorescein mixed isomers, propidium iodide, and 5-HT, all purchased from Sigma Chemical Co (UK). Halothane was purchased from ICI Pharmaceuticals (UK). Stock solutions of the drugs were made in distilled water and kept frozen. Appropriate dilutions were made every day.

Confocal Microscopy
The full length of the basilar artery was dissected and incubated overnight at 4°C in PSS containing 1 mmol/L 5(6)-carboxyfluorescein to stain the extracellular space. The arteries were then mounted on a slide and viewed in the presence of the dye. An Odyssey LSCM (Noran Instruments) was used to obtain stacks of 1-µm optical sections of the regions of interest (x40 water immersion objective, numerical aperture 0.75, Zeiss; argon-ion 488-nm line with a 515-nm long-pass barrier filter). Metamorph software (Universal Imaging Corp) was used for the image acquisition and processing. From each stack, three images corresponding to outer, middle, and inner layers of the media were selected. The angle of orientation of the VSMC with respect to the longitudinal axis of the vessel was measured in 6 to 10 cells per layer, and from it the deviation from 90° was calculated.

To stain the VSMC nuclei, the arteries were fixed with formalin (in 10% saline solution), incubated overnight at 4°C with 10 µmol/L propidium iodide, and washed in PSS for 30 minutes. Stacks of 1-µm optical sections of the regions of interest were taken with the LSCM (x60 oil immersion objective, numerical aperture 1.4, Nikon; argon-ion 529-nm line with a 550-nm LP barrier filter). Metamorph software was used to acquire and process the images and for the 3-D reconstructions.

Wire Myography
Segments of the proximal area of the basilar artery (2 mm in length) were mounted on a wire myograph (Myo-interface, model 410A). Measurements of the vascular morphology were made with a light microscope (x40 water immersion objective, with a filar eyepiece; Zeiss), and the vascular segments were then set to the normalized effective ID of 0.9l₁₀₀ as previously described.¹⁰ After a 30-minute equilibration period, contractile responses to 125 mmol/L KCl (osmotically corrected) and a concentration-response curve to 5-HT (1 nmol/L to 30 µmol/L) were studied.

Statistics and Data Analysis
Vascular responses were calculated in active wall tension (millinewton per millimeter). Sensitivities to 5-HT were determined in terms of pD₂ value (negative logarithm of the concentration required to produce a half-maximal response: pD₂=-log₁₀ EC₅₀), and EC₅₀ values were calculated by computer extrapolation from individual logarithm concentration-response curves.

Results are expressed as mean±SEM, and n denotes the number of animals used in each experiment. Statistical comparisons were made using Student's t test for unpaired experiments, with Bonferroni correction for multiple comparisons. A value of P<.05 was considered significant.

	Results

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VSMC Geometric Disorganization
In the WKY basilar artery, the VSMCs were oriented perpendicular to the longitudinal axis of the vessel with an angle close to 90°. This orientation was constant with depth along the entire length of the artery and was only disrupted at branching points (Figs 1A, 2A, and 3). In every basilar artery from SHRSP, there were two or more localized foci of VSMC geometric disorganization in which this pattern of orientation was altered and the angle of orientation was different from 90° (Figs 1A, 2A, and 3). These VSMC lesions were found only in the SHRSP. In basilar arteries from older (11 months old) SHRSP, there was a significantly greater deviation from 90° of the VSMCs located in layers 1 and 3, next to adventitia and endothelium, respectively, when compared with the WKY strain (Fig 1B). In younger rats (4 months old), the average deviation from 90° of the VSMC located in the lesions was significantly larger in all three layers of the media (Fig 2B). Treatment of the SHRSP with the angiotensin-converting enzyme inhibitor perindopril, which normalized systolic blood pressure,¹¹ had no effect on the geometric disorganization of VSMC lesions (Fig 2B).

View larger version (48K): [in this window] [in a new window]   Figure 1. A, Confocal microscope images of VSMCs located in three different layers ([from left] outer, middle, and inner) within the media of basilar arteries from a WKY (11 months old) and an SHRSP (11 months old). Top panels show the normal orientation of the VSMCs in the WKY, and bottom panels show a lesion within the SHRSP basilar artery. The arteries were stained with the extracellular dye 5(6)-carboxyfluorescein, and the VSMCs were visualized with an Odyssey LSCM. Metamorph software was used for image acquisition and processing. The image dimensions and the localization in the z plane are shown in each panel. Lines with arrows show the longitudinal axis of the vessel. B, Deviation from 90° of individual VSMCs from basilar arteries of 11-month-old WKY and SHRSP. Numbers of animals are given in parentheses. Layers 1, 2, and 3 correspond to outer, middle, and inner VSMC layers, respectively. Results are expressed as mean±SEM; *P<.05, **P<.01 (unpaired Student's t test).

View larger version (49K): [in this window] [in a new window]   Figure 2. A, Confocal microscope images of VSMC nuclei located in three different layers ([from left] outer, middle, and inner) within the media of basilar artery of a WKY (4 months old) and an SHRSP (4 months old). Top panels show the normal orientation of the cell nuclei in the WKY basilar artery, and bottom panels show a lesion within the SHRSP basilar artery. The arteries were stained with the nuclear dye propidium iodide, and the VSMC nuclei were visualized with an Odyssey LSCM. Metamorph software was used for image acquisition and processing. The image dimensions and the localization in the z plane are shown in each panel. Lines with arrows show the longitudinal axis of the vessel. B, Deviation from 90° of individual VSMCs from basilar arteries of 4-month-old WKY, SHRSP, and SHRSP-P. The antihypertensive treatment had no effect on the geometric disorganization of VSMC lesions in the SHRSP basilar artery. Numbers of animals are given in parentheses. Layers 1, 2, and 3 correspond to outer, middle, and inner VSMC layers, respectively. Results are expressed as mean±SEM; **P<.01 (unpaired Student's t test with Bonferroni correction).

View larger version (56K): [in this window] [in a new window]   Figure 3. Distribution of foci of randomly arranged VSMCs in the basilar artery of SHRSP. The schematic diagram shows three of these lesions in the basilar artery of SHRSP and none in that from WKY. Three-dimensional reconstructions of VSMC nuclei located in different areas within a WKY and an SHRSP basilar artery are shown in the center. The 3-D models were reconstructed with Metamorph software from individual stacks of 1-µm optical slices. Image dimensions are as in Fig 2. In the WKY basilar artery, all the VSMCs are oriented perpendicular to the longitudinal axis of the vessel (A), and regions of altered geometric organization are present only at branching points (C). In the basilar artery of the SHRSP, the normal pattern of orientation (B) is disrupted in several regions along the artery. In these lesions, the angle of orientation of the VSMCs differs significantly from 90° (D).

Vascular Remodeling
Basilar arteries of the SHRSP showed increased wall-lumen ratio and wall thickness and reduced internal and external diameters, whereas there was no difference in the cross-sectional area. These features of vascular remodeling¹² were present in the basilar arteries from both old and young SHRSP. In SHRSP-P, wall-lumen ratio and wall thickness were reduced when compared with those in untreated SHRSP (Table).

View this table: [in this window] [in a new window]   Table 1. Vascular Morphology of SHRSP and WKY Basilar Arteries: Effect of Treatment With Perindopril

Responses to Agonists
In the SHRSP arteries, the contractile responses elicited by 125 mmol/L KCl (osmotically corrected) and a concentration-response curve to 5-HT were significantly attenuated compared with these responses in WKY arteries. Perindopril treatment partially prevented this reduction of the contractions (Fig 4). The pD2 values for 5-HT were similar in the three groups of animals (WKY, 7.1±0.02; SHRSP, 6.6±0.16; SHRSP-P, 6.5±0.05), suggesting that the sensitivity of the receptors was not affected.

View larger version (17K): [in this window] [in a new window]   Figure 4. Responses to 125 mmol/L KCl (osmotically corrected) (A) and concentration-response curve to 5-HT (B) in wire myograph–mounted segments10 of the basilar artery from WKY, SHRSP, and SHRSP-P. Numbers of animals are given in parentheses. Results are expressed as mean±SEM; *P<.01 compared with WKY; P<.01 compared with untreated SHRSP (unpaired Student's t test with Bonferroni correction).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
This first study of VSMC orientation using confocal microscopy has shown that in WKY basilar arteries these cells have their long axes oriented perpendicular to the main axis of the artery. The study discovered unique lesions of randomly oriented VSMCs in basilar arteries from SHRSP. This discovery gains significance because two or more of these abnormal regions were present in every basilar artery examined, whereas none was seen in these arteries from WKY. Bundles of longitudinal VSMCs within the medial layers have been described in human mesenteric arteries with conventional histological methods. A greater incidence of these reoriented VSMCs was found in arteries from hypertensive patients and elderly subjects, suggesting a role of sustained high blood pressure and the aging process in VSMC disorganization.^{13 14} In our study, the VSMC lesions were observed in young as well as in old SHRSP rats and were also present in SHRSP-P with normalized blood pressure. These observations argue against the possibility that the disorganized foci are secondary to a blood pressure increase and suggest that these lesions may represent a primary phenotype of genetic origin in this strain of rats.

These abnormal foci resembled branching points in which the VSMCs reorient to form the new artery. The ability to obtain serial optical sections with the LSCM allowed a detailed analysis of the foci in the z plane, showing that there were no branches underneath the regions of disorientated VSMCs. Active angiogenesis has been associated with cerebral ischemia in humans.¹⁵ It is possible that these localized foci observed in stroke-prone rats in our study could correspond to points of angiogenesis leading to the formation of a new branch.

The lesions of randomly arranged VSMCs were observed in arteries that showed decreased lumen and increased wall-lumen ratio, common features in hypertension. The SHRSP basilar artery also showed reduced external diameter and no change in cross-sectional area, suggesting the existence of remodeling, as observed in small arteries from animal models of genetic hypertension and human essential hypertension.⁶ Treatment of SHRSP with perindopril normalized blood pressure and prevented the abnormal wall dimensions observed in nontreated SHRSP basilar arteries. This is in agreement with most of the studies both in humans and SHR, which have shown that antihypertensive treatment results in reverse remodeling.⁶

Altered vascular structure has been proposed to play a role in the enhanced responsiveness observed in resistance^{16 17} and conduit arteries^{18 19} in hypertension.²⁰ In the SHRSP basilar artery, we found decreased contractility despite increased wall-lumen ratio. A reduced contractility of vascular smooth muscle in hypertension has also been reported in both systemic and cerebral arteries in the rat. In 1970, Bandick and Sparks²¹ found an increase in excitability but a decrease in maximum contractile responses of femoral vascular smooth muscle associated with renal hypertension. Five years later, Hansen and Bohr,²² also studying the femoral artery, reported a great reduction in the maximal force development in SHR and mineralocorticoid hypertensive rats. These investigators demonstrated that the decreased contractility was not secondary to the increase in wall tension. Cox²³ made similar studies on carotid and tail arteries of rats with mineralocorticoid hypertension of 2- to 12-week duration. Results were variable depending on the artery and duration of hypertension; however, contractility was significantly reduced in tail arteries after 12 weeks of hypertension.

Four studies evaluating the contractility of cerebral arteries in hypertension have been reported. One of these studied mineralocorticoid hypertension and found no difference between the maximal contractile responses to either KCl or serotonin.²⁴ Three other studies^{25 26 27} dealt with SHR, and all reported reduced maximal force generation to KCl, as we observed in the SHRSP basilar artery. The reduction of the contractions induced by KCl, a nonspecific stimulus, in SHRSP and SHR basilar arteries suggests a decreased vasoconstrictor ability of the smooth muscle cells in the cerebral vasculature of both strains. No satisfactory explanation for the cause of this decrease is evident. Differences between normotensive and hypertensive rats in the biochemical properties of VSMCs could play a role, since it has been demonstrated that the cerebral but not mesenteric vessels from SHR have lower actin and myosin levels compared with WKY.^{28 29} The present study is the first, to our knowledge, in which a maximal force development of vascular smooth muscle of a cerebral artery of SHRSP has been quantified. Compared with the contractility of control muscle, the reduction in the SHRSP was greater than that of any previously reported reductions in contractility of vascular smooth muscle in hypertension. In that sense, the lesions of disorganized VSMCs might contribute to the impairment of contraction, since the cells in these regions might be less efficient at developing force because of the irregular geometric orientation. This is also suggested by the fact that antihypertensive treatment, which did not have an effect on the occurrence of the lesions, did not restore functional responses completely despite significant prevention of the structural remodeling.

The structural and functional alterations reported in this study may have deleterious consequences in the cerebral circulation, especially during hypertension. It is possible that the lesions of disorganized VSMCs could represent regions of weakness in the arterial architecture and potential points of hemorrhage under conditions of extreme high blood pressure, as has been described in the SHRSP strain.⁴

In summary, we have described three abnormalities of the basilar artery from SHRSP: (1) remodeling, (2) decreased contractile force of VSMC, and (3) circumscribed lesions in which the arrangement of the VSMCs is in disarray. The first two of these abnormalities have been frequently reported in arteries from hypertensive animals. The circumscribed lesions that we observed with LSCM have not been previously described. These lesions appear to be age- and blood pressure–independent and may represent a genetic phenotype.

	Selected Abbreviations and Acronyms

 

5-HT = 5-hydroxytryptamine creatinine sulfate LSCM = laser-scanning confocal microscopy PSS = physiological salt solution SHRSP = stroke-prone spontaneously hypertensive rats SHRSP-P = stroke-prone spontaneously hypertensive rats treated with perindopril (2 mg/kg per day from week 8 to week 16) VSMC = vascular smooth muscle cell WKY = Wistar-Kyoto rats

	Acknowledgments

 
This work was supported by grants from the British Heart Foundation (PG 92100 and FS93025), Medical Research Council Clinical Research Initiative in Heart Failure (PG 9307850), and European Community Biomed Program (BMHI-CT93-5262 and BMHI-CT94-1375). Dr Arribas is a Biomed research fellow (BMHI-CT93-5262), and Dr Dominiczak is a British Heart Foundation senior research fellow.

Received September 26, 1995; revision received February 21, 1996; accepted February 22, 1996.

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Arribas, S. M. Articles by McGrath, J. C. Search for Related Content PubMed PubMed Citation Articles by Arribas, S. M. Articles by McGrath, J. C. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB POTASSIUM CHLORIDE