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(Stroke. 1997;28:1028-1034.)
© 1997 American Heart Association, Inc.

Articles

Cerebrovascular Changes in Chronic Hypertension

Protective Effects of Enalapril in Rats

Sukriti Nag, MD, PhD, FRCPC; Daniel W. Kilty, BSc

From the Department of Pathology, Division of Neuropathology, University of Toronto, and the Playfair Neuroscience Unit of Toronto Hospital, Toronto, Canada.

Correspondence to Dr Sukriti Nag, Division of Neuropathology, Toronto Hospital, Western Division, 399 Bathurst St, Toronto, Ontario, Canada M5T 2S8. E-mail nag{at}playfair.utoronto.ca

	Abstract

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Background and Purpose Our recent study demonstrated that in chronic hypertension, hypertrophy of intracerebral arterioles was associated with an increase in the vascular extracellular matrix proteins: fibronectin, laminin, and collagen IV. An additional cerebral finding in chronic hypertension was hypertensive encephalopathy, in which breakdown of the blood-brain barrier (BBB) to serum proteins occurred in multifocal areas of the cortex and basal ganglia. This study was undertaken to determine which of these alterations were attenuated by antihypertensive therapy.

Methods Two weeks after the surgery to produce chronic renal hypertension, half the hypertensive rats were treated orally with enalapril (30 mg/kg), an angiotensin-converting enzyme inhibitor, for 5 weeks. Rats were perfusion-fixed, and their brains were removed and processed for morphological studies. The effect of treatment on vascular hypertrophy was assessed by quantitative morphometry and on the vascular extracellular matrix proteins and BBB permeability alterations by immunohistochemistry.

Results There was increased immunoreactivity for laminin, fibronectin, and collagen IV in pial and intracerebral arterioles of untreated hypertensive rats. Immunoreactivity was greatest in arterioles in areas with breakdown of the BBB to serum proteins. Enalapril treatment for 5 weeks resulted in a significant reduction of the mean systolic blood pressure, which was accompanied by attenuation of vascular hypertrophy and attenuation of changes in the vascular extracellular matrix proteins. In addition, there was reduction in the magnitude of BBB breakdown after treatment.

Conclusions Enalapril treatment had a protective effect and attenuated vascular hypertrophy and the increase in vascular extracellular matrix proteins observed in chronic hypertension. In addition, there was reduction in the magnitude of BBB breakdown.

Key Words: blood-brain barrier • enalapril • extracellular matrix • hypertension • rats • immunohistochemistry

	Introduction

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A consistent finding in chronic hypertension is vascular hypertrophy, which is well documented in cerebral vessels of humans^{1 2 3} and rodents.^{4 5 6} The latter is supported by morphometric studies that demonstrated an increase in wall-lumen ratio of intracerebral vessels of stroke-prone spontaneously hypertensive rats compared with normotensive Wistar-Kyoto rats.⁷ Vascular hypertrophy is associated with an increase in the vascular extracellular matrix, and a recent study demonstrated that this is due to an increase in the proteins laminin, fibronectin, and collagen IV in intracerebral arterioles.⁸

Another complication of hypertension is hypertensive encephalopathy, which is associated with breakdown of the blood-brain barrier (BBB) to serum proteins and protein tracers, in multifocal areas of the cerebral cortex and basal ganglia.^{1 6 8 9 10 11} Several studies demonstrated that the permeability change principally affects intracerebral arterioles^{2 8 9 12} and leads to cerebral edema, which is invariably fatal in the absence of antihyperten- sive treatment. Although there are reports^{13 14} of the effect of antihypertensive treatment on the structure of cerebral vessels, there are no studies of the effect of treatment on the vascular extracellular matrix proteins or BBB permeability alterations.

The present study was undertaken to determine the effects of antihypertensive treatment on cerebrovascular alterations in the temporo-occipital cortex of rats with chronic renal hypertension. The effect of treatment on vascular hypertrophy was assessed by quantitative morphometry, and the effect of treatment on the vascular extracellular matrix proteins and BBB permeability alterations was assessed by immunohistochemistry. The antihypertensive agent used was enalapril, an angiotensin-converting enzyme inhibitor.

	Materials and Methods

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Chronic hypertension was induced in 50 female Wistar rats weighing 120 to 140 g. Rats were anesthetized by an injection of sodium amobarbital (80 mg/kg IP). After a skin incision, a silver clip with a gap of 0.175 mm was placed on the left renal artery, followed by a right nephrectomy. Ten sham-operated rats received the same skin incisions as the test rats, and only the dissections to expose the renal arteries were done. After surgery, 10 rats died of renal failure and were excluded from the experiment.

Two weeks after the surgery to induce hypertension, 15 rats were treated orally with enalapril maleate (Merck Frosst Canada Inc). The drug was dissolved in the drinking water such that rats received a dose of 30 mg/kg per day for 5 weeks. The blood pressure of rats was measured at weekly intervals by a tail-cuff compression method.

Five weeks after the onset of therapy, all rats were killed. Before they were killed, rats were anesthetized by an injection of sodium amobarbital (80 mg/kg IP). A polyethylene cannula, inserted into the femoral artery, was connected to a transducer for measurement of blood pressure and for the removal of blood for determination of blood gases. To achieve maximal dilatation of vessels, as described previously,¹⁵ rats were perfused initially with Krebs' solution for 15 minutes through a cannula in the ascending aorta at a pressure of 120 mm Hg. This was followed by perfusion of fixative that consisted of 3% paraformaldehyde in 0.1 mol/L phosphate buffer (pH 7.2). Brains were removed, and coronal slices of the frontal and temporo-occipital lobes were processed for paraffin-embedding by standard techniques. Sections (5 µm) were stained with hematoxylin and eosin for light microscopic evaluation, and adjacent sections were used for immunohistochemistry.

Immunohistochemistry
The indirect streptavidin-biotin-peroxidase method was used, and sections were treated with 0.5% pepsin for 20 minutes at 37°C before incubation in antisera to collagen IV and laminin (Collaborative Biomedical Products) and fibronectin (Gibco BRL). Dilutions of rabbit antisera to rat proteins used were as follows: collagen IV, 1:600; fibronectin, 1:700; and laminin, 1:750. Sections were incubated in primary antibody overnight at 4°C. After the immunohistochemical reaction, sections were stained with hematoxylin only.

Immunoreactivity was variable in the different experimental groups. These results were expressed semiquantitatively by assigning a score of 1+ to 4+ to the immunoreactivity, as follows: 1+, sparse immunostaining; 2+, mild immunostaining; 3+, moderate immunostaining; and 4+, marked immunostaining. Immunoreactivity was assessed in the coronal sections taken through the temporo-occipital lobes and frontal lobes in a blinded manner, and the assessor was unaware to which group the tissues belonged.

Quantitative Morphometry
Brain blocks from the temporo-occipital cortex were processed for electron microscopy as described previously.¹⁶ This region was selected since arterioles in this area consistently demonstrate BBB breakdown in chronic hypertension. Semithin sections were stained with 1% toluidine blue, and ultrathin sections were stained with uranyl acetate and lead citrate and examined with a Joel CX-100 electron microscope at 60 kV.

Nonpermeable arterioles in layer III of the temporo-occipital cortex were sectioned at a depth of 300 µm from the cortical surface for quantitative morphometry. They had a single layer of smooth muscle cells and external diameters ranging from 15 to 25 µm. Transmission electron micrographs were taken along the circumference of arterioles to obtain the entire cross-sectional area of arterioles at a final magnification of x6120. The cross-sectional area occupied by the media and intima and the luminal area were measured from these electron micrographs with an image analyzer (Leco Instruments Ltd). These measurements were used to obtain a ratio of the wall-lumen area as described previously.¹⁵

Results are presented as mean±SEM. Body weights, mean arterial pressures, and vessel wall dimensions were compared with the unpaired t test.

	Results

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Blood Pressure
The mean arterial blood pressure of sham-operated control rats was 110±3 mm Hg (Table 1). Most rats developed hypertension 2 to 3 weeks after placement of the clip on the renal artery. The mean arterial pressure of untreated hypertensive rats before they were killed was 165±9 mm Hg, a value that was significantly higher (P=.001) than that of normotensive controls. Treatment resulted in a significant reduction (P=.005) in blood pressure, and the mean arterial pressure of treated hypertensive rats was 129±7 mm Hg.

View this table: [in this window] [in a new window]   Table 1. Mean Arterial Blood Pressure, Body Weight, and Vessel Wall Dimensions of Rats in the Different Experimental Groups

The mean arterial pressure of three untreated rats with hypertensive encephalopathy was 176 mm Hg, and that of the three treated rats showing breakdown of the BBB on histological examination was 183 mm Hg.

Vascular Hypertrophy
The mean external diameters of arterioles of normotensive, hypertensive, and treated hypertensive rats were not significantly different (20.6±0.7, 19.6±1.4, and 19.9±1.6 µm, respectively). The degree of mural thickening of intracerebral arterioles of untreated hypertensive rats was mild to moderate by light microscopy. The ratio of the wall-lumen area of arterioles of untreated and treated hypertensive rats is shown in the histogram (Fig 1). The mean cross-sectional areas of the media plus intima and lumen of arterioles of untreated hypertensive rats were 1.27±0.17 and 1.88±0.31 x10² µm², respectively, and the log value of the ratio of the wall-lumen area was -0.16 (Table 1). The latter is significantly higher (P=.001) than the ratio of the wall-lumen area of normotensive rats, which was -0.51. In the case of the treated rats, the areas of the media plus intima and lumen of arterioles were 1.03±0.16 and 2.15±0.32 x10² µm², respectively. The ratio of the wall-lumen area of treated hypertensive rats was significantly lower (P=.02) than that of the untreated rats.

View larger version (37K): [in this window] [in a new window]   Figure 1. Ratio of wall-lumen area of arterioles from untreated (n=10) and treated (n=10) hypertensive rats.

Extracellular Matrix Proteins
Immunoreactivity for collagen IV and fibronectin present in the basement membrane of arterioles of normotensive rats was sparse and similar to our previous observations.⁸ Laminin immunoreactivity present in the endothelial basement membrane and the sarcolemma of smooth muscle cells was greater than that of collagen IV and fibronectin immunoreactivity and was graded as mild (Table 2).

View this table: [in this window] [in a new window]   Table 2. Immunoreactivity for Extracellular Matrix Proteins in Intracerebral Arterioles of Rats in the Different Groups

Nonpermeable arterioles of untreated hypertensive rats showed increased immunoreactivity for the extracellular matrix proteins studied. There was mild increase in immunoreactivity for collagen IV and fibronectin and moderate increase in immunoreactivity for laminin (Fig 2a through 2d). These changes were diffuse, being observed not only in gray matter arterioles but also in arterioles in the white matter and the brain stem (Fig 2e and 2f). Enalapril-treated hypertensive rats showed a decrease in immunoreactivity for the vascular extracellular matrix proteins studied, and immunoreactivity in the nonpermeable cerebral arterioles was comparable to that seen in the arterioles of normotensive rats.

View larger version (124K): [in this window] [in a new window]   Figure 2. Collagen IV and laminin immunoreactivity in intracerebral arterioles from untreated and treated hypertensive rats. Cortical arterioles show 2+ immunoreactivity with collagen IV antiserum in an untreated rat (a) and 1+ immunoreactivity in a treated rat (b). Cortical arteriole of an untreated rat shows 3+ laminin immunoreactivity (c), while the arteriole of the treated hypertensive rat shows 2+ immunoreactivity (d). Similar findings were noted in brain stem arterioles, which showed 3+ laminin immunoreactivity in an untreated rat (e) and 2+ immunoreactivity in a treated rat (f). Panels a through d, original magnification x230; e and f, x350.

Breakdown of the BBB to Fibronectin
Only three of the 15 untreated rats developed hypertensive encephalopathy. Clinically, as observed previously,⁹ these rats appeared lethargic, had limited mobility with rapid respiratory rates, and crouched in the corner of their cage with their eyes shut. The brains of these rats showed diffuse cerebral edema and weighed 2.15±0.14 g, while the mean brain weight of hypertensive rats without cerebral edema was 1.70±0.02 g.

Microscopy showed BBB breakdown to fibronectin in multifocal areas that occupied almost the entire cortical surface of both hemispheres. The areas of BBB breakdown showed extravasation of fibronectin from arteriolar walls into the surrounding neuropil with extension into the underlying white matter and that of the contralateral hemisphere through the corpus callosum (Fig 3a and 3c). The center of some of these areas showed cystic change and a predominantly macrophage response (Fig 3e). The neurons in these areas and the surrounding neuropil appeared normal. A florid astrocytic response was observed in the neuropil around these lesions and in the edematous white matter. Arterioles showed moderate immunoreactivity with fibronectin and collagen IV antisera and marked immunoreactivity with laminin antiserum.

View larger version (137K): [in this window] [in a new window]   Figure 3. Blood-brain barrier alterations in an untreated and a treated hypertensive rat with mean arterial pressures of 186 and 212 mm Hg, respectively. Occipital cortex stained with hematoxylin-eosin from an untreated rat shows a stage II cortical permeability lesion (a), while in a treated rat (b) the only change visible is expansion and pallor of the white matter. Fibronectin immunostaining of adjacent sections clearly shows extravasation of fibronectin in the lesion area in the untreated rat (c), while in the treated rat (d) small areas of perivascular fibronectin immunostaining are present (arrowheads). Higher magnification of the same areas shows a stage II permeability lesion in the untreated rat (e). Note extravasation of fibronectin from arteriolar walls (arrowheads) and a dense inflammatory infiltrate consisting mainly of macrophages. The treated rat (f) shows stage I permeability lesions with fibronectin immunostaining in arteriolar walls (arrowheads) with extravasation into the surrounding neuropil. Neurons in the area show cytoplasmic fibronectin. Panels a through d, original magnification x30; e and f, x230.

All treated rats displayed normal movement and behavior; however, breakdown of the BBB to fibronectin was observed by microscopy in three of the 15 treated rats. Only one of the three rats showed changes in the hematoxylin-eosin stained section, which was in the form of expansion of the white matter (Fig 3b). Immunostaining of the adjacent section with fibronectin antiserum showed a few focal areas with fibronectin extravasation from arteriolar walls into the surrounding neuropil (Fig 3d and 3f). Immunoreactivity for the extracellular matrix proteins was greater in the permeable than nonpermeable arterioles and was graded as mild for fibronectin and collagen IV and moderate for laminin. The other two treated rats showed a few focal cortical areas with gliosis representing remote damage. These areas were readily detected in the laminin immunostained sections that showed crowding of microvessels.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
This study supports our previous observations that in chronic hypertension, hypertrophy of intracerebral arterioles is associated with an increase in extracellular matrix proteins. Enalapril treatment resulted in a significant reduction of the mean arterial pressure, which was accompanied by attenuation of vascular hypertrophy and attenuation of changes in the vascular extracellular matrix proteins. In addition, there was reduction in the magnitude of BBB alterations after treatment.

Vascular Hypertrophy
Vascular hypertrophy, assessed by an increase in the wall-lumen ratio or an increase in the ratio of the wall-lumen area, is well documented in arteries in chronic hypertension in a variety of locations such as mesentery,^{15 17} kidney,¹⁸ and pial arteries of the brain.^{4 13} In this study light microscopy demonstrated vascular hypertrophy diffusely throughout the brain of untreated hypertensive rats, and a reduction in mural thickening was clearly evident in the drug-treated hypertensive rats. Morphometry of arterioles from untreated hypertensive rats showed an increase in the area of the media and intima that encroached into the vascular lumen, resulting in a significant decrease of the luminal diameter and a significant increase in the ratio of the wall-lumen area. The degree of vascular hypertrophy was modest as a result of the short period of observation after the surgery to induce hypertension. Increased wall thickness could be produced by vascular contraction during fixation, and this was overcome by perfusion of Krebs' solution before perfusion of fixative in all groups, as described previously¹⁵ ; this resulted in vascular profiles that were round by microscopy. Since variation in the diameter of arterioles in the different groups could produce similar results, arterioles with external diameters varying between 15 and 25 µm were selected for morphometry, and statistical analysis indicated that the mean external diameter of arterioles in the different groups was similar. The possibility that hypertension resulted in reduction in arteriolar diameters so that larger remodeled arterioles were included in the morphometry is less likely because of the short period of hypertension but cannot be completely ruled out.

The finding that vascular hypertrophy is attenuated by enalapril is similar to the findings of others using a variety of antihypertensive drugs.^{13 14 18 19} Attenuation of vascular hypertrophy was attributed to reduced blood pressure levels and reduced angiotensin II in treated rats, and a similar mechanism may be applicable in this study since the mean arterial pressure of treated rats was significantly lower than that of untreated rats. Others have observed a significant blood pressure reduction in hypertensives after enalapril treatment.^{20 21 22}

Vascular Extracellular Matrix Proteins
There was increased immunoreactivity for fibronectin, laminin, and collagen IV in arterioles of untreated hypertensive rats, with maximal changes occurring in arterioles in the areas of BBB breakdown. These changes are similar to those of our previous study, which also demonstrated that alterations in the vascular extracellular matrix proteins precede permeability alterations.⁸ One other immunohistochemical study reported an increase in collagen IV in human cerebral vessels in chronic hypertension.²³ Alteration in extracellular matrix proteins may be due to vascular distension or stretching^{24 25} or to the direct effect of circulating peptides such as angiotensin II.^{26 27} However, factors other than elevated blood pressure are involved in the observed increase in vascular extracellular matrix proteins in hypertension since this change occurs in cerebral vessels in brain tumors and AIDS,^{28 29} which are unassociated with hypertension. Increase in vascular extracellular matrix proteins should therefore be regarded as a nonspecific response of the cellular components of the vessel wall, specifically the endothelial and smooth muscle cells, to injury.

Decreased immunoreactivity for the vascular extracellular matrix proteins in enalapril-treated rats may be due to reduction in blood pressure or angiotensin II activity. One other study demonstrated that enalapril attenuated increases in collagen and laminin mRNA expression in diabetic glomeruli.³⁰ The mechanism of the protective effect was uncertain; however, possible explanations were reduction in angiotensin II activity or reduction of efferent arteriolar resistance, thus reducing intraglomerular hypertension.³¹

BBB Breakdown
Based on sequential immunohistochemical studies of BBB permeability to endogenous serum proteins, we previously reported permeability alterations of three stages in experimental hypertensive encephalopathy.^{8 9} Early or stage I lesions (Table 3) showed extravasation of serum proteins through arteriolar walls into focal gray matter areas such as the basal ganglia and cerebral cortex, particularly in the arterial boundary zone areas. Permeability changes were unaccompanied by a cellular response. Additional findings in the stage II permeability lesions were central necrosis associated with a macrophage and astroglial response. A variable degree of BBB breakdown was present; however, most cases showed extensive serum protein extravasation from cortical arterioles with spread of protein into the underlying white matter and that of the opposite hemisphere through the corpus callosum. Stage III lesions were remote and consisted of glial scars or cystic cavities lined by astroglia and associated with sparse or no serum protein deposits in the neuropil. Vascular occlusion was not observed in stage I lesions and was occasionally observed in stage II lesions after onset of necrosis. Thus, permeability lesions were differentiated from infarcts in which tissue changes develop after vascular occlusion. Similar observations were made by others.^{6 10}

View this table: [in this window] [in a new window]   Table 3. Stages of Blood-Brain Barrier Breakdown

In this study untreated hypertensive rats showed multiple stage II lesions that occupied almost the entire cortex of the temporo-occipital lobes, while treated rats showed less extensive permeability alterations that were stage I and III lesions. Thus, enalapril therapy reduced the severity and extent of the permeability alterations occurring in hypertension, and the observed lesions were unassociated with cerebral edema or symptoms. This effect was unrelated to the blood pressure–lowering effect of this drug since both the untreated and treated hypertensive rats had similar blood pressure levels.

In this study the angiotensin-converting enzyme inhibitor enalapril was used to define which cerebrovascular changes were affected by antihypertensive therapy. A significant reduction of blood pressure occurred, which was accompanied by attenuation of vascular hypertrophy and attenuation of changes in the vascular extracellular matrix proteins. In addition, there was reduction in the magnitude of BBB alterations in treated hypertensive rats.

	Acknowledgments

 
This study was supported by the Heart and Stroke Foundation of Canada (grant B2401). The authors acknowledge the contribution of Dr David Andrews for statistical analysis and Inge Frohn for paraffin sectioning.

Received August 28, 1996; revision received February 5, 1997; accepted February 5, 1997.

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