微血管内皮大空泡形成对微循环的影响

大鼠肠系膜微血管缺血再灌后内皮细胞出现明显改变,缺血再灌后３０ｍｉｎ～１ｈ细静脉、集合毛细血管内除有白细胞、血小板的粘附以及红细胞聚集、血管内皮水肿外,还发现血管内皮细胞的胞浆形成圆丘形的空泡。空泡从血管内壁内壁突入管腔,空泡直径１０～３０μｍ,多发生在直径２０～７０μｍ的细动脉,静脉内也可出现,但不如动脉多。在同一根血管内可同时出现几个空泡,大的空泡几乎堵塞血管腔。严重者几个空泡出现在同一管腔的周围,造成管腔的堵塞,使血细胞不能顺利通过。结果表明血管内皮大空泡的形成将阻碍血液的流动,加重微循环的障碍和血管周围组织细胞的损伤。     

Clostridium perfringens epsilon-toxin increases permeability of single perfused microvessels of rat mesentery

Epsilon-toxin, the primary virulence factor of Clostridium perfringens type D, causes mortality in livestock, particularly sheep and goats, in which it induces an often-fatal enterotoxemia. It is believed to compromise the intestinal barrier and then enter the gut vasculature, from which it is carried systemically, causing widespread vascular endothelial damage and edema. Here we used single perfused venular microvessels in rat mesentery, which enabled direct observation of permeability properties of the in situ vascular wall during exposure to toxin. We determined the hydraulic conductivity (L(p)) of microvessels as a measure of the response to epsilon-toxin. We found that microvessels were highly sensitive to toxin. At 10 microg ml(-1) the L(p) increased irreversibly to more than 15 times the control value by 10 min. At 0.3 microg ml(-1) no increase in L(p) was observed for up to 90 min. The toxin-induced increase in L(p) was consistent with changes in ultrastructure of microvessels exposed to the toxin. Those microvessels exhibited gaps either between or through endothelial cells where perfusate had direct access to the basement membrane. Many endothelial cells appeared necrotic, highly attenuated, and with dense cytoplasm. We showed that epsilon-toxin, in a time- and dose-dependent manner, rapidly and irreversibly compromised the barrier function of venular microvessel endothelium. The results conformed to the hypothesis that epsilon-toxin interacts with vascular endothelial cells and increases the vessel wall permeability by direct damage of the endothelium.     

Structural heterogeneity within the pulmonary microcirculation of the normal rat

Extra-alveolar microvessels of the rat were described previously as nonmuscular, partially muscular, and muscular (Hislop and Reid, 1978). Based on these structural criteria, the present morphometric results present evidence that mean thickness of the endothelium was significantly greater in the muscular microvessels than in each of the other microvessel categories. The percentage of endothelial surface occupied by attenuated segments (20-30 nm maximal thickness) was greatest in the nonmuscular and partially muscular microvessels. Mean plasmalemmal vesicle diameters were consistent throughout the microvascular units. Vesicle numerical densities, however, were significantly greater in the alveolar capillary endothelium than in endothelia of the nonmuscular, partially muscular, and muscular microvessels. Endothelial vacuoles (diameters greater than 150 nm) were not observed in either the capillaries or the nonmuscular microvessels. Mean diameters and numerical densities of vacuoles observed in endothelia of the partially muscular and muscular microvessels were, however, statistically similar. Subclassification of the partially muscular and muscular microvessels by ultrastructural characteristics as arterioles or venules (Rhodin, 1978; Michel, 1982) served to identify greater numerical densities of vesicles in the endothelium of venules than that of the arterioles. As expected, mean thicknesses of the periendothelial connective tissue spaces varied directly with the relative muscularity of the respective microvessels. Based upon the morphometric data presented in this study, future investigations of pulmonary microvascular functions should include considerations of the observed regional variations of endothelial cell ultrastructure.     

Endothelial heterogeneity in the chick wing bud: A morphometric study

Summary The microvascular endothelium of the chick wing bud at stages 22, 27, and 32 was evaluated by ultrastructural morphometry. The rationale for this study is based on the hypothesis that endothelial cells exhibit variation in structure and function during cytodifferentiation. The microvessels had a luminal diameter range such that they were classified as capillaries. The thin continuous endothelium was devoid of a basal lamina. The endothelium had a very small number of plasmalemmal vesicles; vacuoles were however present for all stages and in some cases were abundant. The temporal findings were that endothelial cell thickness increases, plasmalemmal vesicle densities decrease, and the densities of cytoplasmic vacuoles increase. The spatial results were that endothelial cells in proximal regions of the limb have a greater thickness, contain fewer vesicles and have more vacuoles than those in distal regions. In general, these results indicate that endothelial ultrastructural heterogeneity occurs within a 31/2 day timespan of wing bud development. The discussion considers the results with regard to recent reports on endothelial cell heterogeneity.     

Formation of unique vacuoles in tenotomized rat soleus muscle fibers

The formation of unique vacuoles in tenotomized rat soleus muscle fibers was examined by light and electron microscopy. After tenotomy at both proximal and distal tendons, virtually all muscle fibers underwent characteristic degenerative changes with a disorganization of myofibrils called the central core lesion, but eventually recovered. At 3 days after tenotomy, some muscle fibers showed small vacuoles in the sarcoplasm of the end segments, which were larger in diameter and paler in staining than those of the control fibers in light microscopy. At 5 days, more fibers formed larger vacuoles together with the extensive disorganization of myofibrils. Such vacuole formation was more conspicuous in the distal end than in the proximal end. At 1 week the myofibrillar disorganization was most extensive in the central areas, and vacuoles were considerably enlarged in some fibers to occupy most of the sarcoplasm near the fiber ends. Vacuoles decreased in number and size with time and could rarely be seen at 4 weeks postoperative. In thin-section electron microscopy, the early forms of vacuoles were often connected with the T-system tubules. The limiting membrane of such vacuoles possessed many caveolae, some of which appeared to be continuous with the T-system networks. The vacuole membrane was closely associated with the sarcoplasmic reticulum to form dyadic connections. In later stages, the vacuole membrane was lined in part with the basal lamina. From these findings, it can be concluded that the vacuoles are sarcolemmal in nature and derived from the T-system. The significances of the vacuole formation are discussed with special reference to the mechanism and fate of the vacuoles and their clinical implications.     

Peroxidase Arthritis: II. Lymphoid Cell-Endothelial Interactions During a Developing Immunologic Inflammatory Response

The interaction of lymphoid cells with vascular endothelium was studied during the development of immunologic synovitis in response to repeated intraarticular injections of a heterologous protein antigen. Lymphoid cells emigrated in venules and small veins, both by penetrating the endothelial cytoplasm and by traversing intercellular junctions. Frequent endothelial mitoses were coincident with lymphoid cell emigration. Endothelial cells in the involved vessels increased in number and bulged prominently into the vascular lumen. Endothelial nuclei contained dispersed chromatin and prominent nucleoli; the cytoplasm contained many vacuoles and abundant polyribosomes and rough-surfaced endoplasmic reticulum. Intercellular junctions were numerous and complex. These phenomena were prominent in rabbits studied after 12 to 16 daily injections; they then receded, despite continued antigenic stimulation. In animals studied after 35 or 37 daily injections, the venules appeared relatively normal, and lymphoid cell emigration was observed infrequently. Growth of new vessels was prominent at this stage. The present data do not establish whether the endothelial changes were the cause or the result of lymphoid cell emigration, although the latter seems more likely. Further studies are needed to elucidate the exact nature of these interactions.     

Porphyromonas gingivalis traffics to autophagosomes in human coronary artery endothelial cells

Porphyromonas gingivalis is a periodontal pathogen that also localizes to atherosclerotic plaques. Our previous studies demonstrated that P. gingivalis is capable of invading endothelial cells and that intracellular bacteria are contained in vacuoles that resemble autophagosomes. In this study, we have examined the trafficking of P. gingivalis 381 to the autophagic pathway. P. gingivalis 381 internalized by human coronary artery endothelial (HCAE) cells is located within vacuoles morphologically identical to autophagosomes. The progression of P. gingivalis 381 through intracellular vacuoles was analyzed by immunofluorescence microscopy. Vacuoles containing P. gingivalis colocalize with Rab5 and HsGsa7p early after internalization. At later times, P. gingivalis colocalizes with BiP and then progresses to a vacuole that contains BiP and lysosomal glycoprotein 120. Late endosomal markers and the lysosomal cathepsin L do not colocalize with P. gingivalis 381. The intracellular survival of P. gingivalis 381 decreases over 8 h in HCAE cells pretreated with the autophagy inhibitors 3-methyladenine and wortmannin. In addition, the vacuole containing P. gingivalis 381 lacks BiP but contains cathepsin L in the presence of wortmannin. These results suggest that P. gingivalis 381 evades the endocytic pathway to lysosomes and instead traffics to the autophagosome.     

Rho and rho kinase modulation of barrier properties: cultured endothelial cells and intact microvessels of rats and mice

Previous experiments using cultured endothelial monolayers indicate that Rho-family small GTPases are involved in modulation of endothelial monolayer permeability by regulating assembly of the cellular actin filament scaffold, activity of myosin-based contractility and junctional distribution of the Ca²⁺-dependent endothelial cell adhesion molecule, VE-cadherin. We investigated these mechanisms using both cultured endothelial cells (from porcine pulmonary artery and mouse heart) and vascular endothelium in situ (mouse aorta, and individually perfused venular microvessels of mouse and rat mesentery). Exposure to Clostridium difficile toxin B (100 ng ml⁻¹) inactivated 50–90 % of all endothelial Rho proteins within 60–90 min. This was accompanied by considerable reduction of actin filament stress fibres and junctional F-actin in cultured endothelial monolayers and in mouse aortic endothelium in situ . Also, VE-cadherin became discontinuous along endothelial junctions. Inhibition of Rho kinase with Y-27632 (30 μ m ) for 90–120 min induced F-actin reduction both in vitro and in situ but did not cause redistribution or reduction of VE-cadherin staining. Perfusion of microvessels with toxin B increased basal hydraulic permeability ( L _p) but did not attenuate the transient increase in L _p of microvessels exposed to bradykinin. Perfusion of microvessels with Y-27632 (30 μ m ) for up to 100 min reduced basal L _p but did not attenuate the permeability increase induced by platelet activating factor (PAF) or bradykinin. These results show that toxin B-mediated reduction of endothelial barrier properties is due to inactivation of small GTPases other than RhoA. Rho proteins as well as RhoA-mediated contractile mechanisms are not involved in bradykinin- or PAF-induced hyperpermeability of intact microvessels.     

Neutrophil extravasation in rat mesenteric venules induced by the chemotactic peptide N-formyl-methionyl-luecylphenylalanine (fMLP), with special attention to a barrier function of the vascular basal lamina for neutrophil migration

The present study was performed to investigate morphologically the process of neutrophil extravasation induced by the synthetic bacterial peptide N-formylmethionyl-leucyl-phenylalanine (fMLP) in venules of the rat mesentery by the combined use of intravital microscopy and transmission electron microscopy (TEM). Special attention was given to the interaction of the neutrophils with the endothelial cells and endothelial basal lamina. By intravital microscopy, the rolling and adhesion of leukocytes were observed within 3 min in preparations activated by fMLP. Neutrophils remained in the vascular wall for more than 30 min even after penetration of the endothelium. In this period, neutrophils migrating between endothelial cells and their basal lamina were often observed by TEM. After 40 min application of fMLP, some of the migrating neutrophils parted from the vessel wall into the surrounding connective tissues. There were neutrophils which passed through the small pore of the basal lamina with a cytoplasmic constriction. These findings indicate that the endothelial basal lamina acts as a physical barrier against neutrophil extravasation, thus resulting in the transient retainment of neutrophils beneath the endothelial cells of the venular wall.     

Histogenesis and ultrastructure of pancreatic islet graft microvasculature. Evidence for graft revascularization by endothelial cells of host origin.

In previous studies we have demonstrated that syngeneic and xenogeneic pancreatic islet grafts are revascularized within a 10 to 14-day period after transplantation. With the combined use of intravital and electron microscopy, as well as immunohistochemistry using a set of species-specific or -crossreacting antibodies to endothelial cell antigens, we investigated 1) the origin of the endothelium of the newly formed capillaries in free pancreatic islet isografts (hamster-->hamster) and xenografts (rat-->hamster), and 2) the ultrastructural characteristics of these microvessels. Intravital microscopy demonstrated that newly formed microvessels grow from the vascular bed of the host muscle tissue into the islet grafts. Immunohistochemical analysis of host tissue and transplanted islets with antibodies against factor VIII (recognizing both hamster and rat factor VIII), bovine PECAM-1 (CD31; endoCAM, crossreacting with hamster but not rat PECAM-1), and rat ICAM-1 (CD54, non-crossreacting with hamster ICAM-1) showed that the transplanted rat islets were revascularized by endothelium of hamster (host) origin. At an ultrastructural level, the endothelial lining of the newly formed microvessels showed diaphragmatic fenestration, a characteristic feature of endothelial cells of pancreatic islets in situ. On the basis of these findings we suggest that pancreatic islet transplantation may take a unique position in the field of organ transplantation, since the generally proposed mechanisms of endothelial cell-dependent antigen recognition as a trigger of graft rejection may not be transferred to islet grafts, containing microvessels lined by endothelial cells of host origin.     

The fate of vacuolation in liver cells with special reference to hyaline globules.

This study was undertaken in rats to clarify the mechanisms and time necessary for recovery from vacuolation in liver cells. Vacuoles were produced by congestion of the liver due to constriction of the inferior vena cava just below the diaphragm, and changes in vacuoles were examined quantitatively and qualitatively until 24 h after release of the constriction. Vacuoles in liver cells decreased in number by half within 5 min after recovery from congestion. The remaining vacuoles metamorphosed to hyaline globules by condensation of the contents. The number of hyaline globules increased with a peak occurring at 3-6 h after recovery from congestion, although the number of vacuoles decreased gradually. Only a few small vacuoles and hyaline globules were found in liver cells in pericentral areas at 24 h after recovery from congestion. These data indicate that vacuoles may be discharged promptly from the liver cell cytoplasm after recovery from congestion, and the remaining vacuoles may metamorphose to hyaline globules by condensation of the contents and finally fade into the cytoplasm.     

Maintenance and repair of the lung endothelium does not involve contributions from marrow-derived endothelial precursor cells

Lung endothelium is believed to be a quiescent tissue with the potential to exhibit rapid and effective repair after injury. Endothelial progenitor cells derived from the bone marrow have been proposed as one source of new endothelial cells that may directly contribute to pulmonary endothelial cell homeostasis and repair. Here we use bone marrow transplantation models, using purified hematopoietic stem cells (HSCs) or unfractionated whole marrow, to assess engraftment of cells in the endothelium of a variety of tissues. We find scant evidence for any contribution of bone marrow-derived cells to the pulmonary endothelium in the steady state or after recovery from hyperoxia-induced endothelial injury. Although a rare population of CD45-/CD31+/VECadherin+ bone marrow-derived cells, originating from HSCs, can be found in lung tissue after transplantation, these cells are not readily found in anatomic locations that define the pulmonary endothelium. Moreover, by tracking transplanted bone marrow cells obtained from donor transgenic mice containing endothelial lineage-selective reporters (Tie2-GFP), no contribution of bone marrow-derived cells to the adult lung, liver, pancreas, heart, and kidney endothelium can be detected, even after prolonged follow-up periods of 11 months or after recovery from hyperoxic pulmonary endothelial injury. Our findings argue against any significant engraftment of bone marrow-derived cells in the pulmonary vascular endothelium.     

Vacuole formation in fatigued single muscle fibres from frog and mouse

Force recovery from fatigue in skeletal muscle may be very slow. Gross morphological changes with vacuole formation in muscle cells during the recovery period have been reported and it has been suggested that this is the cause of the delayed force recovery. To study this we have used confocal microscopy of isolated, living muscle fibres from Xenopus and mouse to visualise transverse tubules (t-tubules) and mitochondria and to relate possible fatigue- induced morphological changes in these to force depression. T-tubules were stained with either RH414 or sulforhodamine B and mitochondrial staining was with either rhodamine 123 or DiOC6(3). Fatigue was produced by repeated, short tetanic contractions. Xenopus fibres displayed a marked vacuolation which started to develop about 2min after fatiguing stimulation, reached a maximum after about 30min, and then receded in about 2h. Vacuoles were never seen during fatiguing stimulation. The vacuoles developed from localised swellings of t-tubules and were mostly located in rows of mitochondria. Mitochondrial staining, however, showed no obvious alterations of mitochondrial structure. There was no clear correlation between the presence of vacuoles and force depression; for instance, some fibres showed massive vacuole formation at a time when force had recovered almost fully. Vacuole formation was not reduced by cyclosporin A, which inhibits opening of the non-specific pore in the mitochondrial inner membrane. In mouse fibres there was no vacuole formation or obvious changes in mitochondrial structure after fatigue, but still these fibres showed a marked force depression at low stimulation frequencies (low-frequency fatigue). Vacuoles could be produced in mouse fibres by glycerol treatment and these vacuoles were not associated with any force decline. In conclusion, vacuoles originating from the t-tubular system develop after fatigue in Xenopus but not in mouse fibres. These vacuoles are not the cause of the delayed force recovery after fatigue.     

Studies of the capillary basal lamina. I. Ultrastructure of the red body of the eel swimbladder.

The rete mirabile of the eel swimbladder is a vascular organ in which arterial andvenous capillaries alternate in regular fashion. The endothelium of the arterial capillaries is high, whereas that of the venous capillaries is thin and fenestrated. Endothelial cells and pericytes are the only cells found in the rete. A tubular systemin the arterial endothelial cells is connected with the organelles. The basal laminaeof both capillaries are similiar to those of mammalian capillaries of the same type. They present three layers of different electron density and have a high fibrillar pattern.A fine fibrillar material and dense fibrils appear in the cisternae of the rough endoplasmic reticulum and in large vacuoles of endothelial cells and pericytes: these cells areapparently involved in the synthesis of their lamina. Since the rete mirable ofthe eel swimbladder is a pure vascular preparation, it is most useful for the study of themorphology, the permeability, and the metabolism of the endothelial cells and for the analysis of the chemical structure of their basil laminae.     

Effects of the pyrimido-pyrimidine derivative RX-RA 85 on metastatic tumor cell-vascular endothelial cell interactions

An important step in the metastatic process is the interaction of blood-borne malignant cells with the vascular endothelium. Among the agents that may interfere with this process are pyrimido-pyrimidines, such as RX-RA 85, developed originally as an antiplatelet agent. Using an endothelial cell momolayer attachment assay we have investigated the effects of RX-RA 85 on tumor cell and endothelial cell properties. Exposure of bovine aortic endothelial cells for 3 h to > 4 µg/ml RX-RA 85 produced toxic effects, resulting in vacuole formation, retraction and finally rounding up of the cells. Endothelial cells derived from different sources behaved dissimilarly; human brain, human meninges, mouse brain, mouse lung and rat lung endothelial cells were less sensitive to drug treatment than bovine aortic endothelial cells. RX-RA 85 treatment of bovine aortic endothelial cells increased B16-F1 melanoma cell adhesion. When B16-F1 cells were exposed to 4–8 µg/ml RX-RA 85, increased adhesion to the subendothelial matrix occurred, whereas exposure to higher drug concentrations (8–16 µg/ml RX-RA 85) decreased adhesion. Indirect immunofluorescence staining of cytoskeletal structures in B16-F1 cells adhering to and spreading on matrix revealed that the differential effects of RX-RA 85 on the organization of microtubules and microfilaments might explain the dose-dependent differences in adhesion kinetics.     

Vacuole formation in the endothelium of rat extremity vessels depends on fixation techniques and vessel type

Applying immersion fixation for electron microscopy, huge clear endothelial membrane-bound vacuoles of 0.1-3 microm diameter were noted in the extremity veins of Sprague-Dawley rats. Histological and electron microscopic histochemical methods were applied to determine whether they were the product of programmed cell death or any other kind of cell damage. Image analyzer was used to measure the total area of the vacuoles in the endothelium cells. Neither lipid content nor acidic phosphatase activity could be identified in the vacuoles. In saphenous and brachial veins, the vacuoles occupied 20.6 +/- 2.21% and 18 +/- 2.45% of the endothelium, respectively. Venous endothelium of two different strains of rat also contained the vacuoles. No such structures appeared in extremity arteries. Long-term tilting did not influence vacuolization. Using in vivo whole body fixation, only pinocytotic and dense microvesicles, but no vacuoles were noted. In conclusion, the clear vacuolar structures represent neither lipid inclusions nor secondary lysosomes. The method of tissue fixation is critical when venous endothelial vesicles are investigated. It is presumed that the vacuoles originated from intra- or intercellular microstructures, and that in case of the collapsible vein segments, their size is increased under the pathological-hypoxic and low-pressure-conditions of in vitro fixation.     

Expression of caveolin-1 in human brain microvessels

Caveolae are microinvaginations of the cell plasma membrane involved in cell transport and metabolism as well as in signal transduction; these functions depend on the presence of integral proteins named caveolins in the caveolar frame. In the brain, various caveolin subtypes have been detected in vivo by immunocytochemistry: caveolin-1 and -2 were found in rat brain microvessels, caveolin-3 was revealed in astrocytes. The aim of this study was to identify the site(s) of cellular expression of caveolin-1 in the microvessels of the human cerebral cortex by immunofluorescence confocal microscopy and immunogold electron microscopy. Since in the barrier-provided brain microvessels tight relations occur between the endothelium-pericyte layer and the surrounding vascular astrocytes, double immunostaining with caveolin-1 and the astroglia marker, glial fibrillary acidic protein, was also carried out. Immunocytochemistry by confocal microscopy revealed that caveolin-1 is expressed by endothelial cells and pericytes in all the cortex microvessels; caveolin-1 is also expressed by cells located in the neuropil around the microvessels and identified as astrocytes. Study of the cortex microvessels carried out by immunoelectron microscopy confirmed that in the vascular wall caveolin-1 is expressed by endothelial cells, pericytes, and vascular astrocytes, and revealed the association of caveolin-1 with the cell caveolar compartment. The demonstration of caveolin-1 in the cells of the brain microvessels suggests that caveolin-1 may be involved in blood-brain barrier functioning, and also supports co-ordinated activities between these cells.     

Expression of ICAM-1, VCAM-1, E-selectin and TNF-alpha on the endothelium of femoral and iliac arteries in thromboangiitis obliterans

Immunohistochemical light and electron microscopical analysis of surgical biopsies obtained from femoral and iliac arteries of patients with thromboangiitis obliterans (TAO) were performed to investigate the presence of tumour necrosis factor-alpha (TNF-alpha) and expression of the endothelial cell adhesion molecules intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. Expression of ICAM-1, VCAM-1 and E-selectin was increased on endothelium and some inflammatory cells in the thickened intima in all TAO patients. Ultrastructural immunohistochemistry revealed contacts between mononuclear blood cells and ICAM-1-, and E-selectin-positive endothelial cells. These endothelial cells showed morphological signs of activation. The present data indicate that endothelial cells are activated in TAO and that vascular lesions are associated with TNF-alpha secretion by tissue-infiltrating inflammatory cells, ICAM-1-, VCAM-1- and E-selectin expression on endothelial cells and leukocyte adhesion via their ligands. The preferential expression of inducible adhesion molecules in microvessels and mononuclear inflammatory cells suggests that angiogenesis contributes to the persistence of the inflammatory process in TAO.     

Role of oxidative stress on pathogenesis of hypertensive cerebrovascular lesions

The hypertensive rat brain exhibited softening, severe edema and intracerebral hemorrhage. The NO(2) (-) + NO(3) (-) (NOx) level in the hypertensive rat brain was higher than in the normotensive rat brain. Light microscopy demonstrated severe arterial and arteriolar lesions with fibrinoid deposits and medial lesion. After injecting hypertensive rats with nitroblue tetrazolium (NBT), formazan deposits, which are the reaction product of reduction of NBT by superoxide, were observed in the microvessels and nervous tissue around the microvessels of injured brain. Immunohistochemistry showed that copper zinc superoxide dismutase and manganese superoxide dismutase expression of the endothelial cells of hypertensive rats were also upregulated in comparison with normotensive rat endothelial cells. Inducible nitric oxide synthase and endothelial nitric oxide synthase expression in endothelial cells of normotensive rats were strongly positive, whereas the expression in hypertensive rat endothelial cells was weaker. Nitrotyrosine, a biomarker of peroxynitrite, which is a powerful oxidant formed by the reaction of nitric oxide (NO) with superoxide, was found in the microvessels, injured arteries and arterioles and infarcted brain tissue. Deposition of a major aldehydic product of lipid peroxidation, that is, 4-hydroxy-2-nonenal (4-HNE) was found in microvessels, perivascular tissue, and edematous and infarcted brain. Hypertensive cerebrovascular disease is the result of hypertension-induced oxidative stress.