Segmental arterial mediolysis of the middle colic artery: report of a case with special reference to lesions of small arteries and veins

We report a case of segmental arterial mediolysis (SAM) that involved the middle colic artery, and present some pathologic alterations found in mesenteric small arteries and veins. The patient, a 52-year-old woman, underwent an emergency laparotomy for acute intra-abdominal hemorrhage, and a segment of the transverse colon with hemorrhagic mesocolon was excised. Microscopic examination demonstrated two separate lesions of SAM in the middle colic artery. The involved arterial segments showed a partial to circumferential loss of the media (mediolysis) and intima associated with the formation of a pseudoaneurysm. Smooth muscle cells adjacent to the mediolysis showed various degenerative changes. In addition, we found multiple, tiny foci of degenerative lesions affecting the outer media in the wall of small arteries. Subendothelial vacuoles and nodular intimal proliferation were also noted in small veins. Whereas SAM chiefly affects large or medium-sized arteries, small blood vessels, including veins, are also affected. The present case is unusual in that degeneration of medial smooth muscle cells was clearly observed in the arterial walls, and the small veins were affected by lesions similar to those in arteries. We suspect that a phenotypic modulation of vascular smooth muscle cells induced by some genetic vulnerability plays a role in the pathogenesis of SAM.     

The Cellular Pathology of Experimental Hypertension: VI. Alterations in Retinal Vasculature

The ultrastructure of retinal arterial vessels from rats with severe renal hypertension has been studied. The permeability of retinal vessels has also been examined by means of vascular labeling technics utilizing horseradish peroxidase and microperoxidase as tracer substances. Small retinal arteries and arterioles exhibit foci of smooth muscle necrosis characterized initially by fragmentation of medial smooth muscle cells, and subsequently by loss of myofilaments and release of free vesicles, vacuoles and other cytoplasmic organelles extracellularly. Evidence for increased permeability is observed occasionally in retinal capillaries and less frequently in arteries and arterioles. The enzymatic tracers penetrate the tight junctions of the endothelial cells and are found in the basement membranes adjacent to endothelial and smooth muscle cells, as well as in expanded extracellular spaces around the capillaries. The alterations in the ultrastructure and permeability of retinal vessels in experimental hypertension have been compared with that of visceral and cerebral cortical vessels.     

Role of lysosomes in mesenteric arterial lesions of renal hypertensive rats

The acid phosphatase activities of arterial cells in the mesenteric arteries of renal hypertensive rats were investigated by both light and electron microscopy. Light microscopically, strongly positive acid phosphatase reactions were confirmed in endothelial cells, intimal cells, medial cells and adventitial cells of the mesenteric arteries, together with considerable deposition of fibrinoid substance in the intima and media in contrast to the appearance in control rats. Electron microscopically, lysosomes with acid phosphatase-positive reaction products were increased in number in endothelial cells, intimal smooth muscle cells, medial smooth muscle cells and adventitial neutrophils or macrophages. The lysosomes in intimal smooth muscle cells and those which were extracellularly discharged were responsible for lysis of the fibrinoid substance. In the media, acid phosphatase-positive lysosomes of medial cells and extracellularly discharged matrix lysosomes with acid phosphatase-positive reactions were also involved in the hydrolysis of necrotic substances and extracellular matrix. These acid phosphatase-positive reactions were diminished both light and electron microscopically in endothelial cells, intimal cells, medial muscle cells and adventitial cells in the regions of healing arteries where fibrinoid substance had been degradated and the intima showed cellulofibrous thickening. The possible role of this acid phosphatase activation for the clearance of cell debris as well as exudative substances in the healing of damaged arterial tissue was discussed.     

A comparative study of neuromuscular transmission in several mammalian muscular arteries

Intracellular recordings were made from the smooth muscle of isolated segments of the rabbit ear artery, rabbit saphenous artery, rat tail artery, and guinea pig mesenteric artery. Resting membrane potentials recorded from cells in all these arteries were the same (–65 to –75 mV) and perivascular nerve stimulation evoked excitatory junction potentials (EJPs). At stimulation frequencies>0.2 Hz facilitation of the EJPs was observed in all but the rat tail artery; in this artery the amplitude of the second EJP in a train was less than the first for stimulation frequencies between 0.3 and 2.0 Hz. Spontaneous excitatory junction potentials (SEJPs) at frequencies up to 20/min were recorded during all impalements in the rat caudal artery. In rabbit ear, saphenous and guinea pig measenteric arteries single, supramaximal intensity stimuli evoked EJPs which were not associated with any detectable contraction. Facilitation of EJPs during trains of stimuli >1 Hz gave rise to graded active responses of up to 50 mV in the saphenous and tail arteries whereas all-or-nothing action potentials of 42–50 mV were recorded in both the rabbit ear and guinea pig mesenteric arteries. Such responses were always associated with contraction. Intraluminal distension of the arteries had no effect on the RMP or response to nerve stimulation.     

实验性猕猴椎基底动脉粥样硬化的研究

本研究用高脂饮食喂养猕猴,造型期17个月,取其椎动脉颅外及颅内段、基底动脉和大脑后动脉作光镜、扫描电镜观察。结果发现颅外段椎动脉粥样硬化损害程度较颅内段重,其脂斑数目多,面积大;颅内段也可见大小不等、形态多样的脂斑,但大部分内膜仍较正常;基低动脉损害较轻,内膜仅含2—3层泡沫细胞,但中膜平滑肌细胞已开始变性;大脑后动脉未见有脂斑,但有弥漫性内膜增厚,且超过了中膜的厚度。本研究结果与我们先前报道的同一模型的颈动脉系统比较,发现颈动脉系统的损伤程度更重于椎基底动脉系统,这和人类脑动脉粥样硬化多发生在颈内动脉和Willis环的规律一致,因此我们认为猕猴可作为研究脑动脉粥样硬化的十分理想的动物模型。     

Ultrastructure of an arterial lesion induced in rats by fenoldopam mesylate, a dopaminergic vasodilator

Fenoldopam mesylate (FM) is a dopaminergic vasodilator with demonstrated efficacy and a favourable safety profile in hypertensive and congestive heart failure patients. FM produced a novel arterial lesion in renal and splanchnic arteries of rats, but not dogs or monkeys. The studies reported here were undertaken to investigate the ultrastructure of the arterial lesion induced in rats by FM in an attempt to shed light on its pathogenesis. Rats were infused intravenously with FM, either 50 micrograms/kg/min for 1 or 4 h, or 5 or 100 micrograms/kg/min for 24 h. Control rats were infused for 4 or 24 h with vehicle alone. Perfusion-fixed tissue from the stomach and pancreas of control and drug-treated rats was examined by transmission electron microscopy. No arterial lesions were seen in rats infused with the drug for 1 or 4 h, or in control rats. All drug-treated rats infused with 5 or 100 micrograms/kg/min of FM for 24 h had lesions in subserosal gastric arteries and interlobular pancreatic arteries. In areas of mild arterial damage, medial smooth muscle cells contained intracytoplasmic pseudovacuoles, autophagic vacuoles, and electron-dense, myofilamentous inclusions. More severe lesions were characterized by overt medial necrosis and haemorrhage. The endothelium of affected arteries was invariably intact, except in areas of severe medial damage. The internal elastic lamina and connective tissue elements within the arterial wall were unaffected. These findings suggest that medial smooth muscle cells are the primary site of damage caused by fenoldopam mesylate in splanchnic arteries of the rat. This iatrogenic arterial lesion could provide an interesting model to study the response of medial smooth muscle to pharmacologically mediated injury.     

Ultrastructure of an arterial lesion induced in rats by fenoldopam mesylate,a dopaminergic vasodilator.

Fenoldopam mesylate (FM) is a dopaminergic vasodilator with demonstrated efficacy and a favourable safety profile in hypertensive and congestive heart failure patients. FM produced a novel arterial lesion in renal and splanchnic arteries of rats, but not dogs or monkeys. The studies reported here were undertaken to investigate the ultrastructure of the arterial lesion induced in rats by FM in an attempt to shed light on its pathogenesis. Rats were infused intravenously with FM, either 50 micrograms/kg/min for 1 or 4 h, or 5 or 100 micrograms/kg/min for 24 h. Control rats were infused for 4 or 24 h with vehicle alone. Perfusion-fixed tissue from the stomach and pancreas of control and drug-treated rats was examined by transmission electron microscopy. No arterial lesions were seen in rats infused with the drug for 1 or 4 h, or in control rats. All drug-treated rats infused with 5 or 100 micrograms/kg/min of FM for 24 h had lesions in subserosal gastric arteries and interlobular pancreatic arteries. In areas of mild arterial damage, medial smooth muscle cells contained intracytoplasmic pseudovacuoles, autophagic vacuoles, and electron-dense, myofilamentous inclusions. More severe lesions were characterized by overt medial necrosis and haemorrhage. The endothelium of affected arteries was invariably intact, except in areas of severe medial damage. The internal elastic lamina and connective tissue elements within the arterial wall were unaffected. These findings suggest that medial smooth muscle cells are the primary site of damage caused by fenoldopam mesylate in splanchnic arteries of the rat. This iatrogenic arterial lesion could provide an interesting model to study the response of medial smooth muscle to pharmacologically mediated injury.     

Studies on the healing of arterial lesions in experimental hypertension

Summary Rats made hypertensive by bilaterally constricting their renal arteries were intermittently given antihypertensive drugs to cause their blood pressure to fluctuate; the intima of their mesenteric arteries was then investigated electron microscopically. The intimal fibrinoid degeneration showed a much weaker tendency to heal than that of the previously reported rats treated continuously with antihypertensive drugs (Kojimahara et al., 1971), and the arteries showed marked dysoria associated with endothelial injury and thrombus formation. Endothelial cells that had migrated from the endothelium into the subendothelial space became intimal cell, which after proliferation by mitosis, formed myofilaments in their cytoplasm, turning into fibroblast-like smooth muscle cells (modified smooth muscle cells) in the intima. Thus some of the smooth muscle cells that proliferated in the intima and took part in the organization of the intimal fibrinoid substance were considered to be derived from endothelial cells.     

Cell-to-cell herniae in the arterial wall. I. The pathogenesis of vacuoles in the normal media.

Vacuoles were observed by light microscopy in the smooth muscle cells of the media in normal rat arteries. By electron microscopy these vacuoles were limited by two membranes; they usually contained myelin figures, a few organelles (especially mitochondria and microfilaments), and an amorphous background material that varied greatly in density. Morphologic evidence indicates that these structures arise by herniation of one smooth muscle cell into another; it is presumed that herniation occurs during contraction at weak points corresponding to areas where adjacent cells come in close contact. Such cell-to-cell herniae were mostly seen in small arteries (arterioles) with a diameter of 0.4 to 0.2 mm; however, none was found in coronary arteries of this size. This discrepancy suggests that the pathogenesis of cell-to-cell herniae is correlated not only with the caliber of the artery but also with functional demands. (Am J Pathol 87:375-398).     

Mesenteric arterionecrosis in natural and experimental equine endotoxaemia

To test the hypothesis that mesenteric arterionecrosis (MA) occurs in horses with naturally occurring endotoxaemia (ET) and in those with experimentally induced ET, the mesentery and gastrointestinal tract of 21 Thoroughbred racehorses (15 with spontaneous colic suspected to be due to ET, and six with experimentally induced ET) were examined. MA, which occurred in 13 of the 15 horses with spontaneous colic and in all six of the cases of experimental ET, was morphologically similar in the two groups of animals. This suggested that the pathogenesis of the MA was fundamentally similar in the two groups, and that MA is a pathognomonic feature of equine ET. In addition to histolysis of the arterial walls associated with infiltration of blood components, changes were noted in the medial smooth muscle including formation of many intracellular vacuoles within single smooth muscle cells, cytoplasmolysis, necrosis with granules and vacuoles, and coagulation necrosis; similar changes have been observed in cases of prolonged angiospasm or vasoconstriction. It is suggested that the effects of sustained arterial contraction leading to intimal and medial damage influence the pathomorphogenesis of MA.     

ROLE OF LYSOSOMES IN MESENTERIC ARTERIAL LESIONS OF RENAL HYPERTENSIVE RATS

The acid phosphatase activities of arterial cells in the mesenteric arteries of renal hypertensive rats were investigated by both light and electron microscopy. Light microscopically, strongly positive acid phosphatase reactions were confirmed in endothelial cells, intimal cells, medial cells and adventitial cells of the mesenteric arteries, together with considerable deposition of fibrinoid substance in the intima and media in contrast to the appearance in control rats. Electron microscopically, lysosomes with acid phosphatase-positive reaction products were increased in number in endothelial cells, intimal smooth muscle cells, medial smooth muscle cells and adventitial neutrophils or macrophages. The lysosomes in intimal smooth muscle cells and those which were extracellularly discharged were responsible for lysis of the fibrinoid substance. In the media, acid phosphatase-positive lysosomes of medial cells and extracellularly discharged matrix lysosomes with acid phosphatase-positive reactions were also involved in the hydrolysis of necrotic substances and extracellular matrix. These acid phosphatase-positive reactions were diminished both light and electron microscopically in endothelial cells, intimal cells, medial muscle cells and adventitial cells in the regions of healing arteries where fibrinoid substance had been degradated and the intima showed cellulofibrous thickening. The possible role of this acid phosphatase activation for the clearance of cell debris as well as exudative substances in the healing of damaged arterial tissue was discussed.     

Evidence for frequency-dependent arterial damage in vibrated rat tails

The effects of single 4-hr bouts of continuous 30, 60, 120, and 800 Hz tail vibration (49 m/sec2, root mean squared) were compared to assess frequency-amplitude-related structural damage of the ventral caudal artery. Amplitudes were 3.9, 0.98, 0.24, and 0.0055 mm, respectively. Vibrated, sham-vibrated, and normal arteries were processed for light and electron microscopy. The Curry rat tail model of hand-arm vibration (Curry et al. Muscle Nerve 2002;25:527-534) proved well-suited for testing multiple frequencies. NFATc3 immunostaining, an early marker of cell damage, increased in smooth muscle and endothelial cells after 30, 60, and 120 Hz but not 800 Hz. Increased vacuolization, which is indicative of smooth muscle contraction, occurred for all frequencies except 800 Hz. Vacuoles increased in both endothelial and smooth muscle cells after 60 and 120 Hz. Only 30 Hz showed pronounced smooth muscle cell vacuolization along the internal and external elastic membranes, suggesting stretch-mediated contraction from the large amplitude shear stress. Discontinuities in toluidine blue staining of the internal elastic membrane (IEM) increased for all frequencies, indicating vibration-induced structural weakening of this structure. Patches of missing IEM and overlying endothelium occurred in approximately 5% of arteries after 60, 120, and 800 Hz. The pattern of damage after 800 Hz suggests that the IEM is disrupted because it resonates at this frequency. Vibration acceleration stress and smooth muscle contraction appear to be the major contributors to arterial damage. The pattern of vibration-induced arterial damage of smooth muscle and endothelial cells is frequency-amplitude-dependent.     

Medial changes in arterial spasm induced by L-norepinephrine.

In normal rats, the media of small arteries (0.4--0.2 mm in diameter) previously was shown to contain intracellular vacuoles, identified ultrastructurally as herniations of one smooth muscle cell into another. The hypothesis that intense vasoconstriction would increase the number of such vacuoles has been tested. In the media of the saphenous artery and its distal branch, vasoconstriction induced by L-norepinephrine produced many cell-to-cell hernias within 15 minutes. At 1 day their number was reduced to about 1/10 of the original number. By 7 days the vessel was almost restored to normal. Triple stimulation over 1 day induced more severe changes in the media. These findings suggest that smooth muscle cells are susceptible to damage in the course of their specific function. The experimental data are discussed in relation to medial changes observed in other instances of arterial spasm. Endothelial changes that developed in the same experimental model were described in a previous paper.     

Derivation of intimal cells appearing in spontaneous healing process of hypertensive arterial lesions.

Light and electron microscopic and autoradiographic studies were made on the process of spontaneous organization of fibrinoid substance deposited in the intima, that is, spontaneous healing of intimal fibrinoid degeneration of the hypertensive rat mesenteric arteries at 8–24 weeks after the constriction of the bilateral renal arteries.The organization of the intimal fibrinoid substance by intimal cells was performed mainly from the luminal side and infrequently from the medial side. Indigenous intimal cells and circulating blood cells were not positively involved in the organization.During the organization of fibrinoid substance, the endothelial cells turned into smooth muscle cell-like cells in situ, and there was a picture suggesting the migration of these smooth muscle cell-like endothelial cells into the intima or their incorporation into the intima by the covering of adjacent endothelial cells. Experiments with intravenous administration of ³H-proline revealed that endothelial cells and intimal and medial smooth muscle cells resembled each other functionally. It can therefore be said that the majority of the cells that participate in the organization of intimal fibrinoid substance are intimal smooth muscle cells derived from endothelial cells, and a part of the cells is derived from medial smooth muscle cells. The cellulofibrous tissue of the intima after the complete organization of intimal fibrinoid substance resulted from the proliferation of the endothelial cellderived intimal smooth muscle cells and from the fiber and ground substance formation by these.     

Pathogenesis of Focal Cytoplasmic Necrosis of the Smooth Muscle Cells in Hypertensive Rat Arterial Media

Hypertensive rat arteries exhibited severe medial smooth muscle cell injury and necrosis. Electron microscopic observations showed the smooth muscle cells of these arteries exhibited characteristics of focal cytoplasmic necrosis forming new cytodemarcating membrane between the healthy cytoplasm and necrotic cytoplasm. When the focal necrotic cytoplasm disappeared from the injured smooth muscle cells, it left it with a moth-eaten leaf-like appearance (moth-eaten necrosis). At an advanced stage of injury, smooth muscle cells changed to islet-like cell bodies with newly formed basement membranes around them, and further islet-like cell bodies and cell debris disappeared leaving lamellar and reticular basement membranes.In hypertensive rats injected with nitroblue tetrazolium (NBT), formazan deposits were observed in the medial cells and nitrotyrosine, a biomarker of peroxynitrite, were immunohistochemically observed in the arterial media. Nick-end positive extranuclear small granular bodies, which might have derived from focal necrotic cytoplasm and nucleus, were detected in the arterial media using DNA nick-end labeling method. Based on electron microscopical and histochemical findings, we conjectured that the focal cytoplasmic necrosis of the smooth muscle cells in the arterial media depended on injury arising from mitochondria-derived oxidants.     

The Cellular Pathology of Experimental Hypertension: VII. Structure and Permeability of the Mesenteric Vasculature in Angiotensin-Induced Hypertension

Acute hypertension was produced in rats by the infusion of angiotensin amide for 2 to 4 hours. These animals were injected intravenously prior to sacrifice with either colloidal carbon or iron dextran particles. The mesenteric vessels from hypertensive and control animals were processed for electron microscopy. Ultrastructural alterations are found in dilated segments of small arteries. Initially there is severe contraction of medial smooth muscle cells and the formation of processes of smooth muscle cytoplasm. This is followed by lysis of cell processes and bodies, and passage of plasma and colloidal iron into the media. Subsequently, carbon, platelets, fibrin and cellular debris are seen within these foci of medial necrosis. These changes appear as a sequence whose severity reflects the duration of the angiotensin infusion and degree of elevation of the systolic pressure. The morphologic alterations are discussed in relation to the generalized increase in vascular permeability that is associated with the hypertensive state.     

Enhanced oxygen uptake and lactate production of smooth muscle cell proliferates of rabbit carotid arteries

In rabbit carotid arteries intimal smooth muscle cell proliferations were induced by repeated local electrical stimulation of the artery wall. Oxygen uptake and lactate production of the proliferating tissue were determined in vitro and compared with the results obtained from nonstimulated arterial wall segments. Under the incubation conditions employed, oxygen consumption and lactate production of the proliferating tissue were 91.3 and 62.5 nmol·min^–1·mg^–1DNA, compared with the control values of 70.8 and 41.6 nmol·min^–1·mg^–1DNA. The DNA content of the proliferates and normal arterial wall tissue amounted to 9.6 and 12.0 g DNA·mg^–1 dry weight.The results show that in proliferates obtained with the described procedure there is an increased capacity for ATP regenerating systems, respiration and glycolysis, indicating a modified function of the proliferating smooth muscle cells.     

Declining density of intimal smooth muscle cells and age as preconditions for atheronecrosis in the basilar artery

The aging basilar artery has some differences and some similarities when compared with the aorta and coronary arteries. As the non-necrotic intimal thickness increases over time, the number of smooth muscle cells reaches a steady state around age 25–30 years in the coronaries and aorta, but continues to increase in the basilar artery, even to 90 years of age. The numbers of cells per unit of tissue (the cell density) declines with age, and the patterns of decline are quantitatively similar in all three arterial segments. All arteries so far examined behave alike in showing that atheronecrosis emerges in those specimens that have sufficiently low density of intimal smooth muscle cells. These results identify low intimal cell density as a criterion for recognizing arteries that are prone to atheronecrosis. One possible explanation is that depopulation of the fibrotically thickened and aged intima, by spreading apart the smooth muscle cells with expanding matrix materials, could be the conditioning factor that brings about the intrusion of atheronecrosis.     

Arterial size determines the enhancement of contractile responses after suppression of endothelium-derived relaxing factor formation

We studied the effect of endothelium-derived relaxing factor (EDRF) on norepinephrine-induced contractile responses and on the tissue guanosine-3,5-phosphate (cGMP) concentration of isolated rabbit arteries with an increasing endothelium to smooth muscle cell ratio (aorta, femoral and mesenteric arteries). After suppression of EDRF formation (either by N ^G-nitro-l-arginine or, in mesenteric arteries, by saponin), contractions elicited by cumulative doses of norepinephrine were unaltered in aorta but were enhanced by 22.5% in femoral arteries and by 44.3% in mesenteric arteries (at the highest norepinephrine concentration). The cGMP concentration (pmol/mg protein) of unstimulated, endotheliumintact vessels decreased after suppression of EDRF formation from 1.09±0.24 to 0.74±0.28 in aortic, from 2.86±0.4 to 0.61±0.19 in femoral and from 6.3±0.9 to 0.7±0.15 in mesenteric arterial segments. The basal cGMP concentration did not differ in endothelium-denuded segments of these arteries, suggesting a similar basal activity of soluble guanylate cyclase (sGC). A higher sensitivity of sGC may have contributed to the higher cGMP concentration observed in the smaller arteries, since in the presence of sodium nitroprusside the cGMP concentration of endothelium-denuded segments increased 1.8-fold in aortic, 2.9-fold in femoral and 2.4 fold in mesenteric arterial segments. However, these differences in sGC activation cannot be solely responsible for the high basal cGMP concentration in endotheliumintact mesenteric arteries. The greater ratio of endothelium to smooth muscle cell layers in the smaller arteries might result in a higher EDRF concentration in the vascular wall and subsequently in a higher cGMP concentration. In conclusion, these data support the view of a greater importance of EDRF-mediated vascular control in small arteries than in large conduit arteries.     

Spontaneous arterial lesions: their possible role in arteriosclerosis

Spontaneous lesions of the arterial wall involving the internal elastic lamellae and variable amounts of the intima are described in the spontaneously hypertensive rat caudal, renal, and mesenteric arteries. A simple model for producing similar circumferential lesions in rat and rabbit carotid arteries has been developed and the subsequent repair of these lesions is described. Two types of circumferential lesion can be produced by the application of 50-160 g of longitudinally applied tension. Small lesions can be up to 400 micron in length and are characterized by the loss of a small area of endothelium and rupture of the internal elastic lamellae. No demonstrable damage to the media is detected in these lesions. Larger lesions can be up to 1 mm in length and are characterized by the loss of endothelium and rupture of the internal as well as a variable number of medial elastic lamellae. Little, if any, damage to the medial smooth muscle cells is observed although the extracellular matrix is often disrupted. Small lesions are completely reendothelialized within 24 hr and larger lesions within 7-10 days. Both large and small lesions repair without the formation of an intimal thickening of smooth muscle cells, despite quite marked damage to the media of the larger lesions.