Cytoarchitecture of the smooth muscles and pericytes of rat cerebral blood vessels. A scanning electron microscopic study

The three-dimensional cytoarchitecture of the smooth muscles and pericytes of rat cerebral blood vessels was studied by scanning electron microscopy after removing extracellular connective tissue matrices with the KOH-collagenase digestion method. The tunica media of major intracranial arteries such as the internal carotid, vertebral, basilar, and other cerebral arteries measuring more than 100 microns in outer diameter consisted of spindle-shaped smooth-muscle cells arranged circularly to the long axis of the vessel. Muscle cells at the branching points, however, showed a variety of shapes, sizes, and arrangements. As the vessel size decreased, smooth-muscle cells showed bi- or trifurcations at the cell poles. In the precapillary arterioles, smooth-muscle cells which had helically surrounded the endothelial tubes had bulging cell bodies with various cytoplasmic processes extending from the cell poles. Distinct specializations presumed to be sphincters were not found on the arteries or arterioles. Pericytes of the capillary had become extended along the vessel axis, having fusiform cell bodies with longitudinally oriented long cytoplasmic processes. Cells located periendothelially in the venules and veins were stellate in shape with many cytoplasmic processes which were interwoven to form complicated cellular networks around the endothelial tube.     

Scanning electron microscopy of normal and vasospastic monkey cerebrovascular smooth muscle cells

Normal cytoarchitecture of smooth muscle cells of monkey cerebral arteries was studied using scanning electron microscopy after removal of adventitial connective tissue by hydrolysis with HCl. Cerebral arteries were also examined after contraction in vitro with prostaglandin F2 alpha (PGF2 alpha). Anterior cerebral arteries were studied after exposure for 6 days in vivo to whole blood, oxyhemoglobin, methemoglobin, bilirubin, mock cerebrospinal fluid, or supernatant fluid from an incubated mixture of autologous blood and mock cerebrospinal fluid. Normal smooth muscle cells were spindle-shaped and oriented circumferentially around the vessel. They were often grouped into bundles of 5 to 10 cells; bundles were recognizable because cells within them were joined by multiple intercellular contacts. Groups of smooth muscle cells oriented longitudinally were present outside the circular layers of cells. The adventitial surface of muscle cells was smooth apart from fine longitudinal striations in some areas. Arteries contracted with PGF2 alpha had markedly convoluted and folded cell membranes. Muscle cells of vasospastic arteries and of arteries exposed to oxyhemoglobin and supernatant fluid appeared identical to cells contracted with PGF2 alpha. The outer surface of cells of arteries exposed to bilirubin, methemoglobin, and mock cerebrospinal fluid were normal. Marked similarity between vasospastic smooth muscle cells and smooth muscle cells from arteries contracted with PGF2 alpha suggest that smooth muscle contraction occurs during "vasospasm" due to whole blood and to intrathecal injection of oxyhemoglobin.     

A rat femoral artery model for vasospasm

A new animal model for vasospasm using rat femoral artery has been developed. Whole blood, washed erythrocytes, or leukocytes in platelet-rich plasma were selectively applied to the adventitial surface of the femoral artery for 7 days in 15 rats, after which the vessels were perfusion-fixed and examined by light and transmission electron microscopy and immunohistochemistry. As compared with matched control arteries, there was a prominent reduction in luminal cross-sectional area after 7 days in vessels exposed to whole blood or washed erythrocytes, but not in those exposed to leukocytes in platelet-rich plasma. In arteries with luminal narrowing, light and transmission electron microscopy demonstrated marked morphological changes throughout the vessel wall similar to those seen in cerebral vasospasm after subarachnoid hemorrhage. Immunohistochemistry disclosed a prominent loss of immunoreactive actin in smooth muscle cells of arteries exposed to whole blood or erythrocytes. To assess the time course of arterial narrowing in this model, whole blood was selectively applied to the adventitial surface of femoral arteries in 23 rats for periods from 2 to 20 days. As compared with control arteries, arterial narrowing was variably present at 2 days, progressively increased by 5 days, was maximal at 7 to 10 days, and returned to near control levels by 20 days. The presence and severity of ultrastructural changes in vessel wall corresponded to the degree of arterial narrowing over time. These results suggest that chronic narrowing in rat femoral artery exposed to periadventitial blood is analogous to that observed in cerebral arterial vasospasm after subarachnoid hemorrhage. This new model represents a simple and reliable means to investigate pathogenic mechanisms and potential therapies for vasospasm.     

Effects of radiation on cerebral vasculature: a review

Radiation therapy plays a critical role in the treatment of central nervous system neoplasms and cerebral arteriovenous malformations. The deleterious effects of radiation on cerebral arteries may be the primary limitation to these treatment methods, as radiation may cause a variety of cerebrovascular injuries and hemodynamic changes. Radiation-induced changes in the cerebral arterial wall are determined by a number of cellular processes in endothelium and smooth muscle cells that modulate differences in radiosensitivity and phenotypic expression. The histopathological findings in arterial radiation injury include vessel wall thickening, thrombosis, luminal occlusion, and occasional telangiectases. Mechanisms for radiation injury to blood vessels include phenotypic changes in normal vessel wall cells (especially endothelium) manifested by the expression or suppression of specific gene and protein products that affect cell cycle progression or cellular proliferation or demise via cytotoxic injury or apoptosis. This review describes the molecular and cellular events involved in the systemic and cerebral vascular response to radiation and the potential means by which these responses may be influenced to augment the therapeutic effects of radiation while minimizing the untoward consequences.     

Cyclosporine A-Mediated renal lesion in a child with intractable proteinuria

The histopathological observation of an 8-year-old boy who received cyclosporine A (CyA) for the treatment of persistent proteinuria is presented. In the renal biopsy specimen, typical CyA cytotoxic changes, such as juxtaglomerular apparatus hyperplasia and arteriolar hyalinosis, were observed. Electron microscopically, tubular epithelial cells and arteriolar smooth muscle cells were observed to have enlarged lysosomes, fine vacuoles, and/or enlargement and intracristal swelling of mitochondria. In the area of focal interstitial fibrosis, fibroblast-like cells (myofibroblasts) contained similar cytoplasmic vacuoles with a membranous substance. Although most vacuoles may have been formed due to dilatation of the endoplasmic reticulum, some vacuoles seemed to have originated from mitochondria or autolysosomes in tubular epithelial cells, smooth muscle cells, and fibroblast-like cells. These degenerative changes of organella may take part in the process that resulted in hyalinosis and interstitial fibrosis. Received: March 2, 1998 / Accepted: October 2, 1998     

Shear stress in cerebral arteries supplying arteriovenous malformations

Summary Arteries supplying cerebral arteriovenous malformations (AVMs) are known to dilate with time. These changes are reversible, and the feeders have been shown to slowly decrease in calibre after removal of the AMV. There is evidence that arteries alter their internal diameters in response to sustained changes of blood flow so that shear stress is kept constant. This implies that blood flow-induced shear stress might be the driving force for remodelling of the cerebral vascular network in the presence of an AVM, and for reversion of these changes after radical operation. The objective of this study is to examine the hypothesis that the shear stress in cerebral arteries supplying AMVs is of the same magnitude as in arteries supplying normal brain tissue in spite of larger blood flow rate. Fifteen patients with supratentorial cerebral AVMs admitted for endovascular treatment were examined with transcranial Doppler ultrasound in the distal Willisian vessels. Vessel calibres were measured in angiograms with magnification correction. Shear stress was estimated assuming a constant value for blood viscosity. Corresponding arteries in the cerebral hemisphere with AVM and in the contralateral one were compared in pairs. Thirty-four pairs of homonymous arteries were studied. The arteries on the AVM side presented larger calibres, higher axial blood flow velocities, lower pulsatility index and larger blood flow rates than the contralateral side. There was a clear positive correlation between blood flow velocities and vessel calibres. The estimates of shear stress did not differ significantly in corresponding arteries of both hemispheres (p = 0.18).The results indicate a precise adjustment of cerebral arterial calibre and blood flow-induced shear stress that presumably induces the progressive dilation of AVM feeders, and the slow regression of the vessel calibres to average dimensions after removal of the lesion. Each vessel seems to remodel itself in response to long-term changes in blood flow rate so that the vessel calibre is reshaped to maintain a constant level of wall shear stress.     

Electron Microscopic Studies of Collateral Arteries:An Experimental Investigation in the Rabbit after Occlusion of the Femoral Artery

The ultrastructural changes undergone by collateral arteries during their development were studied in the rabbit after occlusion of the femoral artery. Profound alterations in shape and composition of cytoplasmic components were noted in the endothelial and smooth muscle cells. Signs of high metabolic effort and increased protein synthesis were found in these cells throughout the period of investigation. Early in the development, modified smooth muscle cells made their appearance in the intima, and their possible function is discussed. In the endothelial and smooth muscle cells, as well as in the extracellular space, vacuole-like formations, presumably representing water-containing inclusions expelled from adjacent cells, were noted. In late stages of collateral development there were signs of focal cytoplasmic degeneration in endothelial and smooth muscle cells. Increased pressure and/or flow appear to be responsible for the ultrastructural changes noted in this study. These changes are not specific for collateral arteries, however, but presumably reflect a common reaction of arteries to injury.     

Arterial wall changes in cerebral vasospasm

A right-sided subarachnoid hemorrhage (SAH) was created in 12 monkeys. Only the right (clot-side) cerebral arteries developed angiographic vasospasm (VSP), which was maximal 7 days after SAH. Eight animals were killed at this time and the remainder at 14 days. At the time of killing the middle cerebral arteries (MCAs) were harvested, and four normal, left (non-clot-side) MCAs were vasoconstricted in vitro with prostaglandin F2 alpha. All MCAs were studied with scanning and transmission electron microscopy. Right MCAs in maximal VSP 7 days from SAH were undistinguishable on scanning electron microscopy from normal arteries vasoconstricted in vitro: both groups demonstrated a mean 57% reduction in vessel caliber and a 5-fold increase in vessel wall thickness compared to normal, nonvasoconstricted left MCAs. On transmission electron microscopy, however, arteries in SAH-induced VSP showed degenerative changes in the tunica intima and media. These changes were still evident at 14 days, despite considerable resolution of VSP. These findings, as well as those from other pathological studies of animal and human cerebral arteries in VSP, suggest that the arterial narrowing and vessel wall thickening seen within several weeks of SAH is due primarily to medial contraction, but unlike simple vasoconstriction, is associated with degenerative ultrastructural changes in the endothelium and vascular smooth muscle cells which may denote a temporarily irreversible state.     

The role of hemoglobin in arterial narrowing after subarachnoid hemorrhage

A porcine model for subarachnoid hemorrhage has been developed to allow the selective application of blood and its components to cerebral arteries. Whole blood was centrifuged to produce two fractions consisting of washed erythrocytes (red blood cells, RBC's) and white blood cells (WBC) plus platelet-rich plasma (PRP); the RBC fraction was subsequently separated into hemoglobin (Hb)-containing cytosol and erythrocyte membranes. Each fraction was selectively applied to the middle cerebral artery (MCA) of pigs for 10 days; after which, vessels were perfusion-fixed and examined by light and transmission electron microscopy and immunohistochemical studies. By morphometric analysis, a marked reduction in the MCA lumen cross-sectional area was observed after selective application of RBC's or Hb/cytosol but not of WBC/PRP or erythrocyte membranes. In both RBC- and Hb/cytosol-treated vessels, luminal narrowing was associated with a differential increase in vessel wall thickness of the ventral (subarachnoid) compared to the dorsal (brain) aspect of the artery, but no significant change in cross-sectional area of the vessel wall. After 10 days of exposure to RBC's or Hb/cytosol, there was a spectrum of ultrastructural changes in the vessel wall comparable to those seen after periadventitial application of whole blood. Selective application of commercially available Hb to MCA produced similar structural and morphometric changes. The degree of luminal narrowing after exposure to whole blood or RBC's was proportional to the volume of the erythrocyte mass adjacent to the vessel at sacrifice. These data suggest that arterial narrowing after SAH is mediated by mechanisms related to prolonged exposure of the vessel wall to hemoglobin or its catabolites from lysing subarachnoid erythrocytes.     

Morphological changes of cerebral penetrating arteries in a canine double hemorrhage model

BACKGROUND: Morphological presentations of cerebral vasospasm, such as dystrophy and desquamation of endothelial cells, corrugation of the internal elastic layer, and necrotic changes in smooth muscle cells, are well defined in large cerebral arteries. This study was undertaken to examine pathological changes in cerebral penetrating arteries in a canine double hemorrhage model. METHODS: Eighteen mongrel dogs were subjected to an autologous arterial blood (0.4 mL/kg) injection into the cisterna magna on day 0 and day 2 after withdrawal of an equivalent amount of cerebrospinal fluid. Angiogram was performed on day 0 before the blood injection and on the day the dogs were sacrificed. The dogs were divided into four groups: control (day 0) (n = 4), hemorrhage and sacrificed on day 3 (n = 4), day 5 (n = 5), and day 7 (n = 5). The penetrating arteries were removed and found to be spastic on days 3, 5, and 7, but not in the control group. RESULTS: Endothelial dystrophy and partial desquamation were recorded in all dogs sacrificed on days 5 and 7. Condensation of chromatin, blebbing of the membrane, and condensation of cytoplasm were identified in many endothelial cells, features that are consistent with apoptosis. The morphological changes in the penetrating arteries were more pronounced on days 5 and 7. CONCLUSIONS: Vasospasm occurred in cerebral penetrating arteries in a canine double hemorrhage model. The morphological change in penetrating arteries, especially apoptosis in endothelial cells, is consistent with an early phase of vasospasm. Vasospasm in a penetrating artery may contribute to the cerebral ischemia that occurs during vasospasm.     

The significance of morphological changes in cerebral arteries after subarachnoid hemorrhage

A porcine model was developed to allow quantitative assessment of morphological changes in cerebral arteries after subarachnoid hemorrhage and to determine the significance of structural changes in producing arterial narrowing. Whole blood was selectively applied to the middle cerebral artery (MCA) of seven pigs. After 10 days, vessels were perfusion-fixed and examined by light and transmission electron microscopy and immunohistochemistry. The MCA's exposed to whole blood for 10 days showed prominent luminal narrowing associated with profound ultrastructural changes affecting all layers of the vessel wall. Morphometric analysis, however, demonstrated that significant reductions in the luminal cross-sectional area (-55.8% +/- 12.5%, p less than 0.005) and increases in radial wall thickness (75.1% +/- 10.5%, p less than 0.005) were associated with only minimal increase in the cross-sectional area of the vessel wall (12.5% +/- 15%, p less than 0.025). By stereological analysis, the volume density of individual components of the arterial wall was unchanged in MCA's exposed to blood. Vessels exposed to blood showed a 44% reduction in smooth-muscle cell immunoreactive actin and increased collagen in the extracellular matrix of the vessel wall. These data suggest that structural changes in cerebral arteries after subarachnoid hemorrhage do not directly contribute to vessel narrowing through increases in wall mass. Nevertheless, such changes may reflect pathological mechanisms which act to augment prolonged vasoconstriction or inhibit the maintenance of normal vascular tone.     

Inhibition of experimental vasospasm by pretreatment with ultraviolet light irradiation in a rat femoral artery model

OBJECTIVE: Chronic cerebral vasospasm is resistant to conventional treatments despite recent advances in treatment modalities. We studied the preventive effect of ultraviolet (UV) irradiation on development of vasospasm and its mechanism in a rat femoral artery model. METHODS: The rat femoral artery model for vasospasm was used in this investigation (n = 108). The femoral arteries were divided into four groups: empty and no irradiation (control), UV irradiation (UV group), blood placement (VS group), and blood placement after UV irradiation (VS + UV group). Luminal area was measured, and smooth muscle cell counts in the medial layer of the vessel wall were obtained. An immunohistochemical study was performed with cross sections of fixed femoral arteries at 12 hours and 1, 3, 5, 7, and 49 days after blood placement. The rings of femoral arteries on Day 7 were subjected to pharmacological study. RESULTS: Pretreatment with UV irradiation (VS + UV group) resulted not only in significant inhibition of chronic vasospasm but also in a significant decrease in smooth muscle cells compared with the VS group on Days 5 and 7. The UV-treated arteries (UV and VS + UV groups) exhibited a significant number of Bax- and Bcl-2-positive cells on Days 5 and 7, but few CPP-32 positive cells were observed at the same time points. In the pharmacological study, contractile response to KCI or phenylephrine was reduced significantly in the UV-treated arteries. CONCLUSION: These results imply that UV irradiation prevents chronic vasospasm and suggest that UV-induced cell death plays an important role in the preventive effect without causing complications during the chronic period.     

Apoptosis of endothelial cells in vessels affected by cerebral vasospasm

BACKGROUND: Cerebral vasospasm after subarachnoid hemorrhage is a prolonged contraction that leads to cerebral ischemia or infarction. Morphological studies of cerebral arteries during vasospasm have shown extensive necrosis of smooth-muscle cells and desquamation and dystrophy of endothelial cells. The mechanism of cellular death is unknown. METHODS: We report an observation of apoptotic changes in the cerebral arteries of a patient who died after suffering severe cerebral vasospasm caused by aneurysmal rupture. Subarachnoid hemorrhage and cerebral vasospasm were confirmed by computed tomography scanning and angiogram. Histological and immunohistological examinations for apoptosis were performed in cerebral arteries. For control, the arteries from another patient, who died of trauma without head injury, were used. RESULTS: Corrugation of the internal elastic lamina and increased amounts of connective tissue was demonstrated by light microscopy. Apoptotic changes, characterized by condensation of chromatin of the nucleus and detachment from the basal membrane, were found on transmission electron microscopy in endothelial cells. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling reaction revealed positive staining of the nuclei of the endothelial cells. CONCLUSIONS: This study demonstrates that apoptosis occurred in the cerebral arteries in a patient who died of cerebral vasospasm. The possible role of apoptosis in cerebral vasospasm is discussed.     

Prevention of chronic experimental cerebral vasospasm with ibuprofen and high-dose methylprednisolone

Severe chronic cerebral vasospasm was reliably induced in dogs by two injections, 2 days apart, of autologous blood into the cisterna magna. Treatment with ibuprofen or high-dose methylprednisolone after the first injection prevented or reduced vasospasm. Both drugs reduced meningismus and accelerated the rate of neurological recovery. Compared with specimens from normal dogs, rings of basilar arteries obtained from untreated dogs contracted weakly in response to 5-hydroxytryptamine, prostaglandin F2 alpha, potassium chloride, and barium chloride. Rings of arteries from dogs who received ibuprofen or methylprednisolone contracted more strongly. Electron micrographs of basilar arteries from untreated dogs showed degeneration of smooth muscle, whereas those from treated dogs did not. Thus, what is termed "chronic cerebral vasospasm" probably represents a structural derangement of the blood vessel wall leading to its narrowing, rather than a sustained contraction of the vascular smooth muscle. Administration of high-dose methylprednisolone and ibuprofen can prevent its occurrence.     

Occlusion of the anterior cerebral artery after gamma knife irradiation in a rat

Summary The anterior cerebral artery of rats was irradiated at the level of the circle of Willis by Gamma Knife with a maximum dose of 25, 50, or 100 Gy. Occlusion of the anterior cerebral artery was observed in one rat which was followed for 20 months after irradiation of 100 Gy. Cerebral infarction was found at the midline-frontal region and the cingulate gyrus. Arterial wall thickening with fibrosis, splitting of the internal elastic membrane, luminal organized thrombus, and migration of smooth muscle cells into the thrombus were observed. In the anterior cerebral artery, thrombus formation seemed to occur after the endothelial injury and this may play a prominent role for occlusion. In small arteries, various changes were observed in the irradiated tissue. These included fibrosis and thrombus, thickened smooth muscle layer, lymphocytic infiltration, and thickening of vessel wall with fibrosis and fibrinous thrombosis with leakage of fibrin into the surrounding tissue after different doses of radiation and at different observation times. These changes were comparable to the ordinary vascular response to injury including healing vasculitis and arteriosclerosis.     

Subarachnoid and intracerebral hemorrhage associated with necrotizing angiitis due to methamphetamine abuse--an autopsy case.

The authors report an autopsy case of methamphetamine-related intracranial hemorrhage and vasculitis. A 22-year-old female was comatose after an intravenous injection of an unknown dose of methamphetamine. Computed tomographic scans demonstrated massive subarachnoid hemorrhage and hematoma in the corpus callosum. Cerebral angiography revealed nonfilling of bilateral intracranial carotid arteries and extravasation of contrast medium from the right pericallosal artery which was visualized retrogradely via the vertebral artery. Postmortem studies found cerebral edema, subarachnoid, intraventricular, and intracerebral hemorrhage, and intracranial vasculitis, but no aneurysm or arteriovenous malformation. Necrosis of vessel walls with destruction of the smooth muscle layer, but no leukocytotic infiltration of the vessel walls were observed in all major cerebral arteries. The hemorrhage probably resulted from medial necrosis in the large intracerebral vessels, and a sudden drug-induced rise in blood pressure.     

Perfusion pressure breakthrough threshold of cerebral autoregulation in the chronically ischemic brain: an experimental study in cats.

A study was designed to investigate hyperperfusion syndrome after the restoration of normal cerebral blood flow in a chronically cerebral ischemic state resulting from high-flow arteriovenous malformations or severe carotid stenosis. A fistula between the left distal common carotid artery and the jugular vein was created and the left vertebral artery was simultaneously occluded in 44 cats to produce a chronic cerebral ischemic state. For control experiments, 10 cats underwent occlusion of the left common carotid and vertebral arteries. Six weeks later, pial arterial behavior, disruption of the blood-brain barrier (BBB), and cerebral histological changes were investigated using three experimental methods. In the first, in which a fistula was occluded under normal conditions, pial arteries contracted to some 80% of the resting state; however, no BBB disruption or histological changes were observed. In the second experiment, in which a 20-minute occlusion of the left middle cerebral artery was performed in the cats with a patent fistula, a 30% to 40% dilated state of the pial arteries continued after recirculation, and BBB disruption-induced cerebral edema and infarction were observed. These findings were more prominent in the cats that underwent occlusion of the fistula. On the other hand, in the control group, the pial arteries returned to resting size within 40 minutes, and no BBB disruption or histological changes were observed. In the third experiment, in which moderate hypertension was induced for 1 hour, the pial arteries dilated much more remarkably; BBB disruption and cerebral edema were revealed to be more extensive in the cases of fistula occlusion than within those with a patent fistula. In the control group, however, the pial arteries contracted 10% during hypertension, while BBB disruption and histological changes were not evident. The results indicate that the perfusion pressure breakthrough threshold in the chronically ischemic brain may not be reduced by the restoration of normal blood flow, but may be decreased by the addition of new ischemic insults or hypertension.     

Morphologic changes in cerebral arteries after subarachnoid hemorrhage

The premise of this article is that morphologic changes observed in cerebral arteries after subarachnoid hemorrhage play an important role in the pathogenesis of associated ischemic deficits observed in this disorder. Secondly, the arteriopathic response of cerebral arteries to subarachnoid blood is similar in many respects to that observed in systemic vessels under various pathologic conditions, and common pathogenic mechanisms may exist. The data supporting these premises may be summarized as follows: 1. Morphologic changes in human and animal cerebral arteries after subarachnoid hemorrhage are temporally associated with angiographic and clinically significant vasospasm. 2. Profound morphologic changes in cerebral arteries after subarachnoid hemorrhage do not contribute to structural narrowing of the lumen through increases in vessel wall mass. Nevertheless, structural changes may act in concert with contractile mechanisms to alter normal physiologic responses and maintain a narrowed lumen. 3. The agent responsible for arterial narrowing and morphologic changes in cerebral arteries after subarachnoid hemorrhage is contained in the erythrocyte component of whole blood and is most likely hemoglobin. 4. The volume and duration of exposure of subarachnoid blood to the artery appears to be significant in the development of the angiopathic response. 5. Ultrastructural abnormalities in systemic vessels associated with hypertension, atherogenesis, and endothelial damage are similar in many respects to those seen after subarachnoid hemorrhage.     

Arterial wall changes in early human vasospasm

Histological, histochemical, and histoimmunological studies were conducted on cerebral arteries from three living patients with a recent subarachnoid hemorrhage. There seemed to be a correlation between the severity of vasospasm and the magnitude of pathological alterations. Myofibroblasts and Type V collagen within the medial layer were abundant in vessels showing marked constriction, but were less conspicuous in those arteries showing milder involvement. Intracranial arteries from patients who died from noncerebral causes did not demonstrate these changes. Thus, myofibroblasts and Type V collagen may be related to cerebral vasospasm by holding the damaged vessel in a contracted phase for weeks during the healing period.     

The role of endothelium in cerebral vasospasm

Following subarachnoid hemorrhage, the smooth muscle cells of the major cerebral arteries are exposed to a variety of vasoconstrictor substances, including those liberated from subarachnoid clots in the plasma, released from activated platelets adherent to the damaged endothelium, and released from the injured endothelium. There is no doubt that these vasoconstrictor substances induce the long-lasting contraction of the cerebral arteries. In this article, we discussed supplement mechanisms associated with endothelial damage in the major cerebral arteries with regard to the pathogenesis of vasospasm. Increased permeability in the major cerebral arteries after subarachnoid hemorrhage may allow access of vasoconstrictor and mitogenic substances to the media. These substances may augment the contraction of smooth muscle cells, produce the subendothelial thickening, or both. In addition, the impairment of vasodilatory properties in the major cerebral arteries, including the diminished synthesis of PGI2 and EDRF, as well as the inhibition of EDRF and neurogenic vasodilation by hemoglobin, probably augment the contraction triggered by a variety of vasoconstrictor substances. Furthermore, the impairment of antithrombogenic properties after subarachnoid hemorrhage could participate in the disturbance of cerebral microcirculation and the development of cerebral ischemic symptoms.