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Collagen tripeptide (CTP) is defined as a functional food material derived from collagenase digests of type I collagen and contains a high concentration of tripeptides with a Gly-X-Y sequence. CTP has several biological effects, including the acceleration of fracture healing, ameliorating osteoarthritis, and improving dryness and photoaging of the skin. Recently, an antiatherosclerotic effect of CTP has been reported, although its molecular mechanism is yet to be determined. In this study, we examined the effects of CTP on primary cultured human aortic endothelial cells (HAECs) under oxidative stress, because oxidative endothelial dysfunction is a trigger of atherosclerosis. DNA microarray and RT-qPCR analyses showed that CTP treatment recovered the downregulated expression of several genes, including the interleukin-3 receptor subunit alpha ( IL3RA ), which were suppressed by reactive oxygen species (ROS) treatment in HAECs. Furthermore, IL3RA knockdown significantly decreased the viability of HAECs compared with control cells. RT-qPCR analysis also showed that solute carrier 15 family peptide transporters, which are involved in CTP absorption into cells, were expressed in HAECs at levels more than comparable to those of a CTP-responsive human osteoblastic cell line. These results indicated that CTP exerts a protective effect for HAECs, at least in part, by regulating the recovery of ROS-induced transcriptional repression.

We investigated effect of microgravity environment during spaceflight on postnatal development of the rheological properties of the aorta in rats. The neonate rats were randomly divided at 7 days of age into the spaceflight, asynchronous ground control, and vivarium control groups (8 pups for one dam). The spaceflight group rats at 9 days of age were exposed to microgravity environment for 16 days. A longitudinal wall strip of the proximal descending thoracic aorta was subjected to stress-strain and stress-relaxation tests. Wall tensile force was significantly smaller in the spaceflight group than in the two control groups, whereas there were no significant differences in wall stress or incremental elastic modulus at each strain among the three groups. Wall thickness and number of smooth muscle fibers were significantly smaller in the spaceflight group than in the two control groups, but there were no significant differences in amounts of either the elastin or collagen fibers among the three groups. The decreased thickness was mainly caused by the decreased number of smooth muscle cells. Plastic deformation was observed only in the spaceflight group in the stress-strain test. A microgravity environment during spaceflight could affect postnatal development of the morphological and rheological properties of the aorta.

Background: Recently, the central augmentation index (AIx) has been reported to show a nonlinear correlation with age. We investigated whether the AIx of the central artery changes with the progression of atherosclerosis in Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits., Methods: We simultaneously recorded pressure and flow waves in the ascending aorta in normal and KHC rabbits aged 10-12, 22-24, and 34-36 months, under pentobarbital anesthesia., Results: The systolic, diastolic, and mean arterial pressures and total peripheral vascular resistance were significantly higher in KHC rabbits than in their age-matched controls. The systolic pressure of the KHC rabbits increased with age. Additionally, the AIx of the KHC rabbits was significantly higher than that of their age-matched controls, although the AIx did not show a significant age-dependent increase in either of the two rabbit groups. However, the development of atherosclerotic lesions progressed markedly in KHC rabbits, and the early and late (pulse pressure [PP]) systolic waves increased progressively in amplitude with age in the KHC rabbits. On the other hand, no significant differences were seen in the normal and KHC rabbits' cardiac output (CO), stroke volume (SV), or heart rate (HR) at any age, nor did the two strains show significant age-related changes in these variables. Aortic compliance (SV/PP) was significantly lower in the 22-24- and 34-36-month-old KHC rabbits than in their age-matched controls, and decreased with age in the KHC rabbits., Conclusions: Although the progression of atherosclerosis stiffened the aortic wall, it did not affect the AIx. This was partly the result of the decreased distensibility of the wall, in which the pressure waves used to determine AIx were measured.

Purpose: Pulse wave velocity (PWV) is a direct measure of large arterial stiffness. Augmentation index (AIx) is a surrogate measure of arterial rigidity that could be affected by the ventricular ejection and peripheral haemodynamics in addition to the properties of large arteries. In clinical studies, it is still controversial whether PWV depends on AIx or not. We investigated a relationship between PWV and AIx in young normal rabbits when mean arterial pressure (MAP) level was altered using vasoactive drugs., Materials and Methods: Pulse waves were simultaneously recorded in the ascending, proximal and distal abdominal aortas in response to intravenous infusion of angiotensin II or sodium nitroprusside in fifteen normal rabbits anaesthetized with pentobarbital sodium. Changes in intravascular diameters were measured using an intravascular ultrasound imaging system in the proximal thoracic and proximal abdominal aortas to determine pressure-strain elastic modulus (Ep)., Results: PWV from the ascending aorta to the bifurcation of the common iliac arteries and AIx at the ascending aorta were changed with MAP level in response to vasoactive drugs. Significant and positive correlation was observed between PWV and MAP. AIx was correlated significantly with systolic, diastolic and mean arterial pressures. PWV and AIx showed significant and positive correlation mainly with Ep in the proximal thoracic and proximal abdominal aortas, respectively. There was significant correlation between PWV and AIx (r = 0.66, P < 0.001)., Conclusion: AIx was changed dependently on PWV when the MAP level was changed with vasoactive drugs, which was partly associated with the change in Ep.

To investigate whether the rate of change in blood pressure affects the sensitivity of the aortic baroreceptor afferent response, the change in aortic nerve activity (ANA) to two different rates of ramp increase in mean blood pressure (MBP), elicited by phenylephrine administration, was determined in the rat under urethane (1.5 g kg(-1)) anesthesia. The sensitivity of the increase in ANA following a rapid (average ramp rate, 9.14+/-0.60 mm Hg s(-1), n=11) or gradual (1.78+/-0.24 mm Hg s(-1), n=11) increase in MBP was 2.03+/-0.14% and 1.81+/-0.20% of baseline mm Hg(-1), respectively. These values were not significantly different from each other (P=0.16). Furthermore, we found no correlation between the rate of ramp increase in MBP and the sensitivity of the increase in ANA (r=0.24, P=0.29, n=22). These results suggest that, at least within the normal physiological range of MBP, the rate of the ramp change in blood pressure does not affect aortic baroreceptor afferent sensitivity in the anesthetized rat.

To investigate postnatal developmental changes in functional characteristics of the afferent pathway of the aortic baroreceptor reflex, the responses of aortic nerve activity (ANA) to blood pressure (BP) changes elicited by phenylephrine and sodium nitroprusside administration were tested in 3-, 8- and 20-week-old male rats under chloralose (60 mg kg(-1) i.p.) and urethane (600 mg kg(-1) i.p.) anaesthesia. The function curve of ANA in response to BP changes showed a sigmoid shape that shifted to the right from 3 to 8 weeks of age. The maximal activity and maximal gain of the aortic nerve, which were calculated by a logistic function analysis, were significantly higher in 20-week-old rats (maximal activity, 532 +/- 47% of baseline; maximal gain, 7.9 +/- 0.8% of baseline mmHg(-1); n = 9) than in 3-week-old rats (maximal ANA, 268 +/- 25% of baseline, P < 0.001; maximal gain, 4.9 +/- 0.5% of baseline mmHg(-1), P < 0.01, n = 9) and 8-week-old rats (maximal ANA, 309 +/- 18% of baseline, P < 0.001; maximal gain, 4.9 +/- 0.3% of baseline mmHg(-1), P < 0.01, n = 11). These results suggest that the operating point of aortic baroreceptor afferents is reset to the higher pressure level during development from 3 to 8 weeks of age and, thereafter, the afferent gain increases from 8 to 20 weeks of age. This functional change may be an important factor to prevent an excess increase of BP, which would result in pathophysiological problems.

The effects of microgravity on the histological characteristics of the aortic depressor nerve, which is the afferent of the aortic baroreflex arc, were determined in 10 female adult rats. The rats were assigned for nursing neonates in the Space Shuttle Columbia or in the animal facility on the ground (NASA Neurolab, STS-90), and were housed for 16 days under microgravity in space (microg, n=5) or under one force of gravity on Earth (one-g, n=5). In the Schwann cell unit in which the axons of unmyelinated fibers are surrounded by one Schwann cell, the average number of axons per unit in the microg group was 2.1 +/- 1.6 (mean +/- SD, n=312) and significantly less than that in the one-g group (3.0 +/- 2.9, n=397, p<0.05). The proportion of unmyelinated fibers in the aortic depressor nerve in the microg group was 64.5 +/- 4.4% and significantly less than that in the one-g group (74.0 +/- 7.3%, p<0.05). These results show that there is a decrease in the number of high-threshold unmyelinated fibers in the aortic depressor nerve in adult rats flown on the Shuttle Orbiter, suggesting that the aortic baroreflex is depressed under microgravity during space flight.

The rheological properties of the arterial wall have intimate connections with the fine structure of the wall. Alteration in fine structure due to cardiovascular disease, such as atherosclerosis, could affect the rheological characteristics of the wall. The present study was designed to investigate changes in the static rheological properties of the aorta in Kurosawa and Kusanagi-Hypercholesterolemic (KHC) rabbits aged 10-12, 22-24 and 34-36 months in relation to histological alteration of the wall due to progression of atherosclerosis with age. Circumferential wall strips were excised from the ascending, proximal descending thoracic and proximal abdominal aortas and their stress/strain relationship was recorded. Tensile force of the wall showed a slight but insignificant decrease in the KHC rabbit group aged 10-12 months compared to that in the age-matched control group in the proximal thoracic aorta and increased significantly with ageing in the KHC rabbits in these aortic regions mainly at medium and high strain ranges. Wall stress was significantly smaller in the 10-12 months old KHC rabbit group than in the age-matched control group in the proximal thoracic and proximal abdominal aortas and increased significantly with ageing in the KHC rabbit groups chiefly at medium and high strain ranges. Incremental elastic modulus determined at 50% stretching of the initial length of the wall strip was also significantly lower in the KHC rabbit group aged 10-12 months in comparison to that in the age-matched control group and increased significantly with ageing in the KHC rabbit group. The intima thickened severely with abundant foam cells in the KHC rabbits aged 10-12 months. With increasing age, collagen and elastin fibres showed signs of gradual proliferation among the foam cells. The aortic wall in KHC rabbits was viscoelastic in the relatively early stage of atherosclerosis due to abundant foam cells, and thereafter increased in stiffness gradually with fibrous proliferation and calcification. We can conclude that the static rheological properties of the atherosclerotic aortic wall changed in association with alteration in the microstructure of the wall with progression of atherosclerosis.

Background: Pulse wave velocity, conventionally determined between the carotid and femoral arteries, is a useful measure to estimate stiffness of the aorta. We investigated local pulse wave velocity (LPWV) in different segments in the aorta with relatively early-stage atherosclerosis in relation to the extent and severity of atherosclerotic lesions., Methods: Pressure waves were recorded in eight aortic positions using two catheters with one or two micromanometers to determine LPWV in the ascending aorta, distal end of the aortic arch, proximal, middle, and distal thoracic aortas, and proximal, middle, and distal abdominal aortas in Kurosawa and Kusanagi-hypercholesterolemic (KHC) and normal rabbits aged 10 to 12 months., Results: The LPWV in the KHC rabbit was greatest in the aortic arch, decreased almost to the normal level in the middle and distal thoracic aorta, increased in the proximal abdominal aorta, and showed almost identical change to that in the normal rabbit in the middle and distal abdominal aortic regions. There was significant difference in LPWV in the aortic arch, proximal thoracic, and proximal abdominal aortas between the two rabbit groups. The sclerotic lesion was prominent in the aortic arch, proximal thoracic aorta, and proximal abdominal aortas. The wall was severely thickened with abundant foam cells. The significant increase in LPWV would be mainly related to the increased wall thickness in these aortic regions., Conclusions: We can conclude that LPWV reflects well the distribution and severity of atherosclerotic lesion and the increased wall thickness in the local aortic region in which pulse waves were traveled.

Hydrostatic pressure gradients due to the gravitational force in blood vessels disappear under conditions of microgravity during spaceflight, and the ability of the baroreceptor reflex to control arterial pressure and blood distribution may be altered. We hypothesized, on the basis of the results obtained in our previous experiments using the head-down tilt method in rats and rabbits, that the range of increase in arterial pressure caused by animal behavior narrows under conditions of microgravity, affecting the development of high-threshold unmyelinated fibers in the rat aortic nerve which sends signals from baroreceptors located in the aortic wall to the reflex center. We verified this hypothesis using 9-day-old rat neonates housed with their dams for 16 days on the space shuttle Columbia in outer space (STS-90, Neurolab Mission). Age-matched neonatal rats with the dams remained on the ground as controls. After breeding was carried out in the three experimental groups (FLT, spaceflight; AGC, asynchronous ground control; VIV, vivarium ground control), specimens of the 25-day-old rats were excised and five left aortic nerves in each group were examined by electron microscopy. The number of aortic unmyelinated fibers was significantly less in the FLT group than in each ground control (mean+/-S.D.; 139+/-37 in the FLT, 207+/-36 in the AGC, 283+/-121 in the VIV; P<0.05), which may be related to the weakness of the baroreceptor reflex under conditions of microgravity in space. This result may contribute to understanding of the several cardiovascular issues which occur under microgravity and after reexposure to gravity in human.

The present study was performed to investigate the effects of the development of atherosclerosis on foot-to-foot pulse-wave velocity (PWV) from the ascending aorta to different positions along the aorta in Kurosawa and Kusanagi-Hypercholesterolemic (KHC) rabbits aged 10-12 and 22-24 months old, in relation to the percentage fractional lesioned area (PFLA) in different aortic regions through which the pulse wave travels, as well as the rheological and pathohistological properties of the aortic wall. PWV, when measured in the KHC rabbit from the ascending aorta to each aortic position, showed the highest value on passage through the aortic arch, decreased with conduction to the distal thoracic aorta, reached the minimal value on passage to the distal thoracic aorta or to the middle abdominal aorta in the 10-12- and 22-24-month-old animals respectively, and increased gradually on conduction to the iliac artery. PWV at all aortic regions examined was significantly greater in the 22-24-month-old than in the 10-12-month-old KHC rabbits. PFLA, when measured in the aortic region from the ascending aorta to each aortic position, was maximal in the aortic arch and decreased gradually towards the peripheral aorta in both age groups. PFLA in the 22-24-month-old group was significantly greater than that in the 10-12-month-old group in all aortic regions examined. The atherosclerotic aortic wall showed a significantly lower elastic modulus in the young KHC rabbits compared with age-matched normal rabbits. A significantly higher elastic modulus was observed in the older KHC rabbits compared with that in the younger animals of both strains, associated with the progression of sclerosis. These findings indicate that the increase in PWV is due mainly to an increase with aging in the extent and severity of atherosclerosis in vessels in which the pulse wave travels.

Under microgravity environment, blood shifts headward and thereafter decrease in volume to adapt to the environment, which could affect cardiovascular hemodynamics and their regulatory mechanisms. Baroreceptor sensitivity is known to be reduced in newborn animals and to gradually increase with development. The baroreceptor is a stretch receptor; therefore its function is closely related to the rheological properties and fine structure of the aortic wall in which the baroreceptor lies. The mechanical and histological properties could be altered under microgravity conditions in the process of development with change in circulatory function. In the present study, we investigated the mechanical tensile characteristics and histological structure of the aortic wall in the proximal thoracic aorta of premature rats bred in the microgravity environment of the space shuttle for 16 days.

Introduction: To study development of the aortic baroreflex mechanisms under conditions of microgravity, we carried out the various experiments in the neonate rats aged 25 days raised in microgravity for 16 days (flight: FLT group) in Neurolab program (STS-90, space shuttle Columbia, launch date: Apr 17, '98. Some results of the experiments were already reported. The results of histological examination of the aortic nerve which is the afferent of the aortic baroreflex showed that the number of unmyelinated fibers in FLT was significantly less in than those in two control groups and there was no difference between FLT and each control group in the analysis of myelin. In the present paper, the frequency distribution of axon diameters of the left aortic nerves in FLT was compared to that in two ground control groups to examine the growth of the aortic nerve fibers in space., Methods: After breeding Sprague-Dawley rats for 16 days in the shuttle in space and in the animal center in the Kennedy space center, a total of 43 deeply anesthetized rats were perfused with 1% parahormaldehyde and 1% glutaraldehyde or 4% parahormaldehyde solution buffered at pH7.4 with 0.12 M phosphate solution. Concerning the control groups, one group was the asynchronous ground control (AGC) group in which the rats were housed in the same cages as those on the shuttle, and the other was the vivarium ground control (VIV) group in which the rats were housed in commercial cages. The cervical region of the left aortic nerve which is a branch of the vagus was cut off and stored in the same fixative as that used for perfusion, and postfixed in the solution of 1% OsO4, for 2 hours within 24 hours after the perfusion. The fixed specimens were embedded in epoxy resin blocks by the usual method for electron microscopy following dehydration. Electron microscopic montages of transverse sections of these nerve trunks were made from the five left aortic nerves in each group. The magnification of the montages was approximately 13400 times. The long and short axes (a and b) of the nerve fibers and the myelin thickness (T) were measured with a caliper and the axon diameters (R were calculated by following formula: R2=[(a-2T)2+(b-2T)2]/2.

To study development of the aortic nerve baroreflex under conditions of microgravity, we examined the cross section of the left aortic nerve (LAN), which is the afferent of the baroreflex, in the neonate rats aged 25 days raised in microgravity on the space shuttle Columbia (flight:FLT group) for 16 days. In this paper, we report a part of the result obtained from the data of the myelinated fibers of LAN analyzed with an electron microscope. Two kind of ground control groups were compared to the FLT group; one was asynchronous ground control (AGC) group where the rats were housed in the same cage as that on the shuttle, and the other was vivarium(VIV) group where the rats were housed in a commercial cage. The LANs in each group were extirpated the from rats perfused with a fixative and embedded for histological analysis. We observed the transverse sections of LAN and took pictures of several areas (magnified to x 2K to x 200K). No irregular myelination was found in all fibers of FLT group when they were compared with two control groups. The thickness of myelin of the maximally myelinated fibers were 0.55 +/- 0.17 micrometer in FLT(n=5), 0.45 +/- 0.10 micrometer in AGC(n=5), and O.47 +/- 0.06 micrometer meter in VIV(n=5). There was no significant difference among three groups (unpared t-test). The results suggest that there is no effect of space environment on the myelin formation of each nerve fiber in the aortic nerve.