The direct cause of hypertensive intracerebral hemorrhage is the plasmatic arterionecrosis, characterized by the development of histolysis as well as fibrin (fibrinoid substance) deposition caused by blood plasma insudation in the wall of the intracerebral arteries with preceding necrosis of medial smooth muscle cells. The arterionecrosis produced intracerebral microaneuysms, which were subjected to a diapedetic hemorrhage, eventually leading to the rupture of them. The microaneurysms were sometimes occluded by thrombi and saved from rupture. But the occluded ones were one of the causes of cerebral infarction.
The cerebral arteriess of hypertensive rats with bilaterally constricted renal arteries showed the lesions closely resembling the arterionecrosis. The development of medial smooth muscle cell necrosis, which was the earliest change of the lesions, was inhibited by an atherogenic diet containing cholesterol and lard.
In the small intracerebral arteries, which occaionally showed the arterionecrosis, there were seen intimal lipoidosis, the lipoidosis superimposed with secondary proliferation (arteriosclerosis), and atherosclerosis resulted from necrosis and disintegration of foam cells. But atherosclerosis resulted from fatty swelling and disintegration of increased collagen fibers, which was frequently seen in the proximal segments of cerebral arteries, was not found in the small intracerebral arteries.
Morphological comparison between the arterionecrosis and atherosclerosis of intracerebral arteries was carried out. The arterionecrosis might be considered as the acute type of arteriosclerosis with marked alteration and insudation in the wall and with a little lipid deposition.
When the clamps constricting the bilateral renal arteries were removed in hypertensive rats, their arterionecrosis was healed and transformed into arteriosclerosis.
From the analytical viewpoint of arteriosclerosis, arterionecrosis, and inflammation, it was presumed that comparative studies on various arterial lesions including arteritis, taking their pathogenesis into consideration, would contribute to arteriosclerosis research.

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Electron microscopic observation was made on ultrastructural changes of the extracellular matrix during the development of experimental arteriosclerosis produced in rabbits by partially constricting the carotid artery with a silver cylinder. The initial lesion, within a few days after constriction, was intimal edema, by which the extracellular matrix in the subendothelial layer appeared to be destructed. During this time, smooth muscle cells were observed migrating through the gaps of the internal elastic lamella from the media into the intima. By 5 days when the intimal edema was reduced, proteogylcans in the ground substance were regenerated, as evidenced by increase of the ruthenium red-positive material consisting of particles attached to each other by fine filaments. It was noted the basal lamina-like material accumulated beneath endothelial cells and around smooth muscle cells derived from the media. The basal lamina-like material stained positively with ruthenium red and periodic acid phosphotungstic acid staining, but was shown to be resistant to chondroitinase or hyaluronidase digestion.
Small elastin aggregates that were demonstrated clearly with tannic acid stain, presumably representing the initial stage of elastogenesis, appeared in the basal lamina-like material around the smooth muscle cells. There was no evidence indicating that the microfibrillar components accumulated invariably prior to the elastin aggregtaes. The small elastin aggregates coalesced with adjacent ones to form larger masses which were surrounded by the microfibrils. Based upon such an elastogenic process, staining properties and unsusceptibility to elastase digestion, the peripheral microfibrils of elastic fibers were thought to be a glycoprotein, distinct from the centrally located elastin.
Collagen fibers also were formed within the basal lamina-like material around smooth muscle cells. They appeared commonly in association with the microfibrils, but rarely intermixed with elastic fibers. In the advanced stage of arteriosclerosis collagen fiber bundles and large elastic fibers were seen deposited alternately around the smooth muscle cells, suggesting the periodic secretion of collagen and eastlin from one and the same smooth muscle cell.

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Cholesteryl esters and phospholipids are the major lipids involved in the process of atherogenesis in human as well as experimental atherosclerosis, since they both increasingly accumulate in the tissue as the lesion advances. To elucidate the role of phospholipids in atherosclerosis, we have studied phospholipid metabolism by injecting 50μCi of ¹⁴C-lecithin in the form of sonicated emulsion into 15 fasting rabbits with an average body weight of 3042g.
¹⁴C-Lecithin emulsions were readily incorporated into serum lipoproteins of VLDL plus LDL and HDL fractions separated by the method described by Sakagami-Zilversmit. Specific activities (S. A.) of ¹⁴C-lecithin both in VLDL plus LDL, and HDL fractions showed a die-away curve of two phases whose first phase was a rapid decrease in 10 hours, and the second phase a slower decrement having a turnover time of 22 hours for VLDL plus LDL and 29 hours for HDL, respectively. Radioactivities also appeared in cholesteryl esters of lipoproteins immediately after incorporation of ¹⁴C-lecithin into VLDL plus LDL and HDL, probably due to LCAT in blood serum. The S. A. of cholesteryl esters in VLDL plus LDL attained at its peak 3 hours after injection, and those in HDL 1 hour after injection, then both gradually decreased with a turnover time of 39 hours for VLDL plus LDL, and 31 hours for HDL. Ratios of S. A. of cholesteryl esters over phospholipids were 2.28 in VLDL plus LDL at 48 hours and 1.63 in HDL at 10 hours.
¹⁴C-Lecithin was also incorporated into aotric tissues from serum lipoproteins. The uptake curve of S. A. consisted of three phases: the first phase was a steep rise in S. A. of phospholipds within one hour, the second relatively rapid decrement in 3 to 6 hours, then the third almost stationary, slow decrease in about 48 hours. From cholesteryl ester fractions of aortic tissue, no significant counts were gained, thus the S. A. ratios of cholesteryl esters over phospholipids observed in serum lipoproteins were not maintained in the tissues.
These results indicated that ¹⁴C-lecithin emulsions were rapidly incorporated into serum lipoproteins and were subjected to the fatty acid transferring activities of LCAT in blood serum. ¹⁴C-Lecithin was also taken up by the aortic tissues. However, the uptake in the normal aortic tissues with an integrated endothelium occurred predominantly on the basis of molecular exchange between serum lipoproteins and aortic tissue lipids, rather than a penetration of serum lipoproteins in a particulate form across the cell walls.

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In order to investigate the uptake of serum lipoprotein families into rabbit aortic wall, intima of thoratic aorta was incubated with C-cholesterol labelled lipoproteins in the Warburg Apparatus for 2 hours. Then, radioactivity of the tisuue was determined by the utilization of liquid scitillation counter.
Following conclusions were drown from obtained results.
1) Active transport through the endotherial cell, such as pynocytosis, seems to be a most suggestable mechanism on the uptake of serum lipoproteins into the arterial wall. Furthermore, there may exist regulation system related related to the lipoprotein uptake which regulates the quality and quantity of the lipoproteins. Then, uptake and release of HDL were much easer than those of LDL.
2) In the renovascular hypertension, in vivo, uptake of the lipoproteins increased significantly. In this case, not only the arterial pressure and tension affect to the lipoprotein uptake but also cathecholamine such as noradrenaline may play the important role. However, effect of angiotensin II on the lipoprotein uptake seems to be minor.
3) Immunological reaction caused by the administration of bovine serum albumine increased lipoprotein uptake in vivo. Furthermore, uptake of the lipoproteins into the aortic wall significantly increased in vitro. It may be concluded that the immunological reactions injure the arterial wall and progress the atherosclerosis.

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Twenty persent glucose solution in 500ml water was administered to 131 patients with hypertension, diabetes mellitus or heart disease, any of whom did not suffered from infection, cancer or renal failure; and only 500ml water was administered to 13 healthy persons and to 6 diabetics.
The serum, the urine and the saliva were obtained hourly or continuously before and after the glucose or water administration.
Total binding hexose (TBH) of each body fluid was measured according to the method of Sato (Toshiko) devised for serum total protein-bound hexose.
Experiment 1
Results obtained are as follows:
1) The mode of hourly changes of TBH in the serum, the urine and the saliva were different between the glucose administration and the water one.
2) A significant difference was found among the relationship of the hourly changes of these TBHs by glucose administration to ageing, to glucose tolerance and to aortic arch calcification.
Experiment 2
Fractionation of TBH was performed by sephadex G-100 column chromatography in the serum, the urine and the saliva of 5 healthy persons in order to investigate whether these TBHs of the 3 body fluids were the same substance or not, with the following result: The TBHs of the 3 body fluids were not the same, as the fractionated patterns of the 3 fluids differed from each other.
Experiment 3
The extract of the intima and media of the aorta was gotten by using 0.02M NaCl with pH 6.8. The fractionated pattern of the extract TBH was similar to that of the serum TBH, though different from that of the urine TBH and the saliva TBH.
Comment and conclusion
Ageing, diabetes mellitus and aortic arch calcification have been regarded as similar factors to arteriosclerosis by many investigators.
However, according to our results from the view point of TBH, these 3 arteriosclerotic factors are not the same biologically and mechanically.

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In an attempt to clarify the role of risk factors in the development of arterial calcification in the aged, correlations between the aortic calcification and risk factors such as age, sex, degree of osteoporosis, hypertension, glucose tolerance, Ht, serum cholesterol and triglyceride were obtained by using analysis of variance.
It was found that the correlation between the degree of osteoporosis and the aortic calcification was most prominent and the correlation coefficient between these two parameters was largest. These results demonstrate the intimate correlation between the aortic calcification and osteoporosis in the aged and further suggest the possibility that Ca is transferred from bone to the aorta with age.
In order to prove the possible transfer of Ca from bone to the aorta with age, Ca⁴⁵ content in the aorta before and after the administration of dihydrotachysterol was measured in rats, in which the whole skeleton was previously labelled with Ca⁴⁵. Administration of dihydrotachysterol has been shown to develop an osteoporosis and aortic calcification in rats and it is considered as a model of premature aging. It was found that the aorta of rats treated with dihydrotachysterol contained substantial amount of Ca⁴⁵, thus demonstrating the transfer of Ca⁴⁵ from bone to the aorta.
It is possible that with age Ca is transferred from the bone to the aorta.

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Histological investigation of medial smooth muscle cells in aorta of rabbits fed with cholesterol and biochemical study of contractile protein extracted from human atherosclerotic aortae stripping adventitia were reported in this paper. At the initial stage (within a week) of cholesterol feeding to rabbits, materials stained by Sudan III were observed histologically in the intima of aorta, suggesting that infiltration of lipid due to the cholesterol feeding to the aorta directly bathing with plasma. In the following early stage, smooth muscle cells in the media located adjacent to the intima, which were originally arranged parallel each other to the endothelial surface, were found to be arranged perpendicularly to the surface and to be going to migrate through intimal elastic lamina to the intima. After 1-2 weeks smooth muscle cells accumulated in the intima and they changed to so called “foam cells” probably due to phagocytosis of lipid. And, it was demonstrated in electron microscopic study using Ishikawa's method that the migrating smooth muscle cells and the foam cells in the intima which are thought to be first cellular response in atherosclerotis contained intracellularly the characteristic myogenic filaments in a definite arrangement. Biochemical study of contractile protein extracted from atherosclerotic arteries clarified that myosin and actin content constituting the protein and the Ca²⁺ sensitivity of the protein decreased as the diseases advanced.
The evidence did support the idea as regard to the initial cause of pathogenesis of atherosclerosis that infiltration of lipid in plasma into the arterial wall may result in migration of the medial smooth muscle cells into the infiltrative area before subsequent histological manifestation of the disease.

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