Tunica media changes in the spontaneously hypertensive rat (SHR)

The histological, ultrastructural, morphometrical and histochemical aspects of the arterial media were studied in young and aged SHR, and compared to normotensive Wistar Kyoto rats. The diffuse thickening was the most characteristic feature of the hypertensive media. It seems due to three processes: Early generalized hypertrophy of smooth muscle cells (smc); connective matrix neogenesis and smc proliferation, more evident in peripheral vasculature. The present paper discusses the following hypertensive tunica media changes in relation to the atherosclerotic process: the decrease in lipolytic esterase and cholinesterase activities; the activation of some lysosomal enzymes; the increase in collagen, glycosaminoglycan and elastin content; the increased media thickness; the modified smc behavior (migration, secretion, proliferation). These alterations might positively influence arterial susceptibility to atherosclerosis through reduced smc lipolytic activity; slowed transmural diffusion; perturbed efflux and aggravated media hypoxia.     

Mechanisms underlying hypertrophic remodeling and increased stiffness of mesenteric resistance arteries from aged rats

The mechanisms associated with structural and mechanical alterations of mesenteric resistance arteries from aged rats were investigated by using pressure myography, confocal microscopy, immunofluorescence, and picrosirius red staining. Arteries from old rats showed: (i) increased wall and media thickness, greater number of smooth muscle cell (SMC) layers but decreased density of SMC; (ii) increased number of adventitial cells; (iii) hypertrophy of nuclei of SMC and endothelial cells; (iv) increased stiffness associated with increased total collagen content and collagen I/III deposition in the media; and (v) similar content but changes in elastin structure in the internal elastic lamina. Hypertrophic outward remodeling in aged rat resistance arteries involve adventitial cells hyperplasia, reorganization of the same number of hypertrophied SMC in more SMC layers leading to thickened media and endothelial cell hypertrophy. Fibrosis associated with collagen deposition and changes in elastin structure might be responsible for the increased stiffness of resistance arteries from aged rats.     

Mechanoreception by the endothelium: mediators and mechanisms of pressure- and flow-induced vascular responses

Mechanoreception, a widely distributed sensory modality, has been shown to be present in certain blood vessels. Changes in physical forces, like sudden increase of transmural pressure or flow velocity (shear stress), trigger changes in blood vessel diameter; the former reduces it while the latter increases vessel caliber. These changes in diameter, which are the result of contraction and relaxation of vascular smooth muscle in the blood vessel media, can serve the purpose of physiological regulation of blood flow (autoregulation) and protection of the intima against damages from high shear forces. The precise location of mechanosensor(s) and the mechanism of mechanoreception and signal transduction are poorly understood. Accumulating evidence suggests that the endothelium may be a site of mechanoreception and that changes in the synthesis/release of endothelium-derived relaxing (EDRF, EDHF, PGI2) and contracting factors (EDCF) result in altered vascular smooth muscle tone and vessel caliber. Increased shear stress stimulates the release of EDRF and PGI2 probably via activation of a K+ channel (inward rectifier) in endothelial cell membrane. Endothelium-dependent vascular contraction evoked by increased transmural pressure may be the result of (1) reduced release of EDRF (canine carotid artery) and (2) stimulation of the release of a still unidentified EDCF(s) (feline cerebral artery). Thus the endothelium can serve as pressure and flow sensor and is capable of transducing changes in mechanical forces into changes of vascular smooth muscle tone by modulating the release of endothelium-derived vasoactive factors. The physiological importance of the mechanoreception by endothelial cells in the intact circulation remains to be determined.     

Ultrastructural changes in mesenteric arteries from spontaneously hypertensive rats. A morphometric study

Morphometric measurements at the electron microscope level were carried out on three categories of mesenteric arteries representing elastic (superior mesenteric), muscular and arteriolar vessels, from 10- to 12-week-old spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto normotensive rats (WKY). Changes were observed only in muscular and arteriolar vessels of SHR, mainly as thickening of the vessel wall due to hypertrophy of the media. In muscular arteries, hypertrophy of the endothelial cells, widening of the subendothelial space, increased volume of the internal elastic lamina (IEL), and both hyperplasia and hypertrophy of the smooth muscle cells (SMC) in the media contributed to the wall thickening. In arteriolar vessels, increase in the subendothelial space and IEL, and hyperplasia of the SMC in the media were involved in the increased thickness of the vessel wall. There was no difference in the collagen content in all vessels, but elastin was increased in the muscular and arteriolar vessels of SHR. Nerve density was also increased in arteriolar vessels of SHR. These changes, especially the increase of SMC in muscular and arteriolar vessels, may be related to the elevated blood pressure in SHR.     

Studies on aorta during development. I. Fetal rabbit aorta under ex vivo and in vitro conditions: rapid changes in smooth muscle cell phenotype, cell proliferation and cholesterol content with organ culture

The structural development of the already well defined fetal rabbit aortic wall from 22 to 31 days of gestation in vivo consists of increasing aortic wall thickness, elastic lamina continuities, extracellular matrix deposition, and maturing of the fine structure of the medial smooth muscle cells. In vivo at term (31 days), the mature aortic smooth muscle cells demonstrated the characteristic thin, thick and intermediate filaments, dense plaques, endoplasmic reticulum, golgi, plasmalemma vesicles and an incomplete basal lamina. The fetal aorta rapidly responded to organ culture with various changes. Fetal smooth muscle cells modified their phenotype to the synthetic state when cultured in both serum-supplemented and serum-free media. This smooth muscle cell modification occurred after 3 days of culture in fetal explants. The synthetic type smooth muscle cells (fetal) began to proliferate after 6 days of culture. This proliferation resulted in a peripheral outgrowth after 9 days of 10-20 layers in fetal cultures from serum-supplemented media and of 2-4 layers in serum-free media. The orderly arrangement of the internal elastic lamina and alternating medial layers of smooth muscle cells and elastic lamina seen in vivo was disrupted along with increased matrix after 9 days of fetal explant culture. Significant numbers of 'modified' synthetic phenotype smooth muscle cells were not observed in adult aortic explants until after 15 days in culture in serum supplemented media. The mature contractile phenotype smooth muscle cell predominated in adult explants cultured in serum-free media. Significant synthetic phenotype smooth muscle cell proliferation only occurred in adult explants after 15 days culture in serum-supplemented media. When compared to aorta in vivo evidence for increases in cholesterol esterification were observed in both fetal (9 days) and adult (15 days) explants cultured in both serum-supplemented and serum-free media. The fetal aorta in organ culture appeared to be more susceptible than the adult aorta to (a) phenotypic modulation of smooth muscle cells to the synthetic state, (b) smooth muscle cell proliferation, and (c) early cholesteryl ester accumulation.     

Venous Reactivity in Canine Renovascular Hypertension

The responsiveness of arterial smooth muscle to vasoactive stimuli is enhanced hypertension. It is however, unclear whether this increased reactivity is a generalised property of vascular smooth muscle, involving veins as well. We examined the responses of rings of cephalic veinin vitro taken from 11 dogs with chronic renovascular hypertension and 10 normal dogs. Mean blood pressure was 129 ± 3 mmHg in the hypertensive dogs, 26% above control. Veins from hypertensive dogs had steeper passive circumference-tension relationships than veins from normal dogs, indicating reduced compliance. Sensitivity (defined as location of EC₅₀) to potassium depolarisation was unchanged, but maximal contractile force (Fmax) developed was 35% greater in hypertension when compared with normotensive dogs. With noradrenaline and the selective alpha₁-adrenoceptor agonist methoxamine, there was no difference between normotensive and hypertensive dogs in either location of the EC₅₀ or in the Fmax. With the selective alphaz-adrenoceptor agonist UK 14304, there was a tenfold decrease in sensitivity in hypertension when compared with normotensive dogs, but no change in Fmax. There was, however a tenfold increase in sensitivity to serotonin in hypertension when compared to normotensive dogs, and a 22% increase in Fmax. Contractile responses to transmural sympathetic nerve stimulation were similar in the two groups. As desipramine caused equal increases in responses to neural stimulation, there was no demonstrable abnormality of neuronal uptake in hypertension. Morphometric examination showed no change in media thickness, media thickness/radius ratios or media cross sectional area in hypertension. Therefore, veins from dogs with chronic renovascular hypertension are stiffer but not hypertrophied, and exhibit some specific differences in contractile responses to vasoconstrictor agents when compared with veins from normotensive dogs.     

Cellular hypertrophy in mesenteric resistance vessels from renal hypertensive rats

To determine whether the increased thickness seen in media of mesenteric resistance vessels of Wistar-Kyoto rats made hypertensive by a Goldblatt procedure (one-kidney, one clip model) was due to hypertrophy or hyperplasia of smooth muscle cells, the cellular dimensions of these vessels were estimated using a new, unbiased stereological method (the disector). Furthermore, to investigate whether the changes seen could be secondary to the increased blood pressure, morphometric measurements were also made in renal arcuate arteries, which, due to the constricting silver clip, probably had not been exposed to the increased pressure load. Vessels were mounted on a myograph, and their media thickness, lumen diameter, and maximum active wall tension response were measured. In the mesenteric vessels media thickness had increased by 58%, whereas no changes were seen in the renal vessels. Vessels were then fixed, and serial sections were made in the mesenteric vessels. The disector was used to calculate the numerical cell density in each vessel. By combining the myograph measurements and the estimated numerical cell density, the number of cells per segment unit length was calculated (renal hypertensive rats, 6.8 micron-1; sham-operated Wistar-Kyoto rats, 6.3 micron-1; p greater than 0.40) and mean cell volume was determined (renal hypertensive rats, 1541 micron 3; sham-operated Wistar-Kyoto rats, 1256 micron 3; p less than 0.02). No morphometrical changes were found in single sections of the renal arteries. We conclude that the increased media thickness observed in mesenteric resistance vessels of one-kidney, one clip Goldblatt hypertensive rats mainly was caused by smooth muscle cell hypertrophy.     

高血压大鼠脑血管功能损害的临界关闭压评价

目的通过临界关闭压(CCP)动态观察高血压脑微动脉平滑肌的收缩程度与形态改变间的关系。方法对照组和高血压组大鼠各80只,在高血压形成术后的不同时间点,分别测定脑血管CCP、脑血流自动调节下限(LLCA)和脑血管形态变化。结果高血压组大鼠的CCP逐渐升高,到14、16周明显高于对照组(P<0.05)。CCP的升高与平均动脉压、微动脉中膜厚度及LLCA呈正相关(P<0.05),并且在血压升高初期和血压较高后变化明显,呈倒“S”形改变(P<0.05)。结论高血压大鼠脑微动脉平滑肌的收缩程度明显增强,是微动脉中膜增厚的功能表现,并且在血压升高初期和血压较高后改变比较明显。     

高同型半胱氨酸对高血压大鼠血管平滑肌细胞GRP78和CHOP的表达的影响与血管重构的关系

目的：观察同型半胱氨酸（Homocysteine,Hcy）对高血压大鼠内质网应激因子GRP78和CHOP表达及血管中层厚度变化,探讨Hcy对血管重构的影响。方法：采用腹主动脉缩窄术建立高血压大鼠模型,术后两周采用无创尾套法测量大鼠血压,选取24只成年雄性大鼠[平均动脉压（MAP）〉150mmHg]随机等分为2组,即对照组和蛋氨酸组,每组12只（n=12）。对照组给予普通饮食＋双蒸水灌胃,蛋氨酸组给于30g/L蛋氨酸饮食＋双蒸水灌胃;根据实验结束的时间,又将各组分为4W和8W两个亚组,各亚组6只（n=6）。用同型半胱氨酸检测仪检测血清同型半胱氨酸浓度,用颈动脉插管法测定各组大鼠的MAP,并利用图像分析软件测量血管中层的厚度;HE染色观察大鼠主动脉血管形态学变化;通过免疫组化及Western blot检测大鼠主动脉血管平滑肌细胞（VSMCs）组织中GRP78及CHOP表达水平。结果：①对照组大鼠血清Hcy浓度在正常值范围（〈10μmol／L）;蛋氨酸组大鼠血清Hcy浓度明显高于对照组（P〈0．01）。②两组大鼠MAP均显著增高,4周时两者之间差异不明显,8周时两者差异显著（P〈0．05）;③蛋氨酸组大鼠血管平滑肌中层厚度显著大于对照组（P〈0．05）;④HE染色显示,与对照组相比,蛋氨酸组大鼠主动脉VSMCs显著肥大,管壁显著增厚;⑤两组CRP78和CHOP蛋白表达量增高,与对照组相比蛋氨酸组表达更明显。结论：高同型半胱氨酸可能通过促使高血压大鼠动脉VSMCs内质网应激反应,导致CRP78及CHOP的平衡失调加剧,从而引起血管损伤加重,而发生血管重构加重。     

Effect of vasoactive agents and applied stress on the albumin space of excised rabbit carotid arteries

Experiments were undertaken on excised rabbit common carotid arteries to assess whether the distribution volume for radioactively labelled albumin is influenced by smooth muscle tone or externally applied stress. In arteries at relaxed length and zero transmural pressure, the distribution volume in the media was reduced by noradrenaline at concentrations exceeding 10(-9) M and increased by both sodium nitrite and isosorbide dinitrate at concentrations exceeding 10(-4) M. The distribution volume was lower in both the media and adventitia of segments at in vivo length pressurized with air to prevent convection through the wall, than in segments at relaxed length and zero transmural pressure. Noradrenaline decreased and sodium nitrite increased the medial distribution volume of the tracer in these air-pressurized segments. The vasoactive agents did not change the [51Cr]EDTA space in vessels at relaxed length and zero transmural pressure, although there were small alterations of medial water content. Transient conditions raise interpretative difficulties because of uncertainty about endothelial permeability and time-dependent changes of wall properties. The changes of the distribution volume for labelled albumin are thought to reflect changes in the properties of the interstitium.     

Histologic studies on normal and persistent ductus arteriosus in the dog

The process of anatomic closure of the ductus arteriosus was studied at the ultrastructural level in 15 normal beagles (age 0 hour to 13 days) and in 18 specimens from a strain of dogs with hereditary persistent ductus arteriosus (age 4 hours to 27 days). Normal ductal closure takes place from the pulmonary artery to the aortic end. It is accompanied by a series of histologic changes: 1) separation of the endothelial cells from the internal elastic lamina resulting in a wide region of subendothelial edema; 2) ingrowth and infolding of endothelial cells and migration of undifferentiated smooth muscle cells from the inner media into the subendothelial region; 3) apposition of endothelial cells bordering the lumen; and 4) degenerative changes. In persistent ductus arteriosus, these changes do not occur. The endothelial cells remain closely adhered to the internal elastic lamina and the underlying media is abnormal in structure. In the case of partial persistent ductus arteriosus (ductus diverticulum), both the normal and the abnormal type of wall are found in a single ductus arteriosus. The histologic features of the normal and the persistent ductus arteriosus in the dog resemble those of the normal and the persistent ductus arteriosus in humans, suggesting a similar pathogenesis.     

Relation between lipopolysaccharide-induced endothelial cell injury and entry of macromolecules into the rat aorta in vivo

Lipopolysaccharide (LPS) causes endothelial cell injury both in vitro and in vivo. It is widely believed that this injury in vivo enhances the transport of macromolecules from plasma into the interstitial space of the underlying artery wall. A new technique was used in rats to obtain high resolution transmural profiles of macromolecules in vivo. We compared the time course of the macromolecular transport into the aortic tissue in vivo after LPS injection to that of LPS-induced endothelial cell death and the proliferative response of the endothelium to LPS injury. At a dose of 1 mg LPS/kg body wt, endothelial cell death reached a maximum by 36 hours after LPS injection and remained elevated for 96 hours; the peak of the S phase of endothelial cell proliferation was observed 48 hours after injection. To examine the effect of LPS on macromolecular accumulation, we measured aortic intimal and medial transmural concentration profiles of horseradish peroxidase (HRP) after circulation of HRP for 15 minutes. The data revealed a transient increase in total aortic accumulation (reflecting predominantly the media), which was maximal between 12 and 48 hours after LPS injection. Although total medial accumulation was found to return to near control levels by 72 hours after LPS injection, intimal accumulation remained elevated above control levels for 120 hours. When HRP was added to the perfusate of an in situ aorta preparation at a near zero transmural pressure gradient, the resulting transmural concentration profiles across aortas from control rats and from rats given LPS 24 hours previously were indistinguishable, whereas a pressure gradient of 60 mm Hg revealed LPS-altered concentration profiles analogous to those in vivo. This suggests that the accumulation of HRP observed in vivo was driven by increased convective transport. These results reveal that LPS enhances entry of macromolecules into the aorta wall in vivo. The changes in macromolecular transport do not, however, correlate temporally with endothelial cell death or proliferation. The results are consistent with an LPS-induced decrease in the endothelial barrier function, which precedes, and may be independent of, cell death and a transient increase in convective transport across the media due to alterations in the barrier function of the internal elastic lamina.     

Quantitative morphology of arterioles from the hamster cheek pouch related to mechanical analysis

The structure of 20 second-order arterioles from the hamster cheek pouch was quantitated after histological fixation at physiological pressures. Dilated and contracted vessels with respective internal diameters of 66 ± 9.2 and 30 ± 9.1 μm (SD) were studied. Electron microscopy of four dialted arterioles revealed a combined intima-media thickness of 3.2 ± 1.5 μm with the following composition determined by stereological point counting: endothelial cells (20%), endothelial basement membrane (3%), a continuous elastic lamina (8%), smooth muscle cells (49%), and medial extracellular space (20%). Light microscopy of whole mounts of cheek pouches and isolated arterioles stained with hematoxylin was used to measure orientation and lengths of both smooth muscle and endothelial cell nuclei. The smooth muscle orientation was not significantly different in dilated or contracted arterioles. For all of the muscle orientation measurements combined, the mean pitch angle was 1.1 ± 5.9° (N = 1000) with respect to the circumferential axis of the vessel. Comparison of dilated and contracted arterioles indicated a significant decrease in the muscle cell and nuclear length, but no detectable change in either orientation or nuclear length of the longitudinally oriented endothelial cells. Wall areas measured from transverse sections of dilated and contracted vessels did not change upon contraction. Stereological estimates of relaxed smooth muscle cell length averaged approximately 60 μm. The manner in which structural parameters affect arteriolar mechanical properties is discussed, and it is concluded that, in hamster pouch arterioles, over 99% of the developed smooth muscle force is transmitted circumferentially.     

内皮细胞脂质过氧化损伤增强主动脉平滑肌细胞表达细胞周期素D

为探讨细胞周期素Ｄ在主动脉平滑肌细胞中的表达规律，揭示动脉粥样硬化中平滑肌细胞的增殖机制，在培养在兔主动脉平滑肌细胞中分别加入了同程度的内皮细胞损伤后的条件培养在２４ｈ分别收集各组的平滑肌细胞，进行免疫组织化学染色和细胞核的增殖试验，结果发现，主动脉平滑肌细胞可表达细胞周期素Ｄ，其免疫反应产物主要位地细胞核内，内皮细胞损伤后的条件的培养基能量产滑有细胞表达细胞促进平滑肌细胞的增殖，以上结果提示主动     

Adrenergic mechanisms and remodeling of subcutaneous small resistance arteries in humans

BACKGROUND: Vascular structural alterations in small resistance arteries of patients with essential hypertension (EH) are mostly characterized by inward eutrophic remodeling. In fact, no difference in the smooth muscle cell volume (CV) between normotensive subjects (NT) and essential hypertensive patients was observed. However, experimental models of hypertension with chronic infusion of agonists of adrenergic receptors were characterized by the presence of smooth muscle cell hypertrophy or hyperplasia. Recently, we have observed the presence of vascular smooth muscle cell hypertrophy in patients with renovascular hypertension. OBJECTIVE: The aim of the study to investigate the structural characteristics of subcutaneous small resistance arteries of NT, of EH, and of patients with phaeochromocytoma (Phaeo). PATIENTS AND METHODS: Thirty Phaeo, 30 NT and 30 EH were included in the study. A biopsy of subcutaneous fat was taken from all subjects. Small resistance arteries (relaxed diameter 160-280 microm) were dissected and mounted on a micromyograph and the media : lumen ratio was calculated. In nine Phaeo, nine NT and 13 EH the cell volume was measured by an unbiased stereological principle, the 'disector' method.RESULTS No difference in smooth muscle cell volume was observed between groups. However, inward remodeling in Phaeo was less marked than in EH, although the increase in media : lumen ratio was similar compared with NT. However, the lack of changes in media cross-sectional area, compared with NT, suggest that there has been little hypertrophy, the changes observed thus being eutrophic. CONCLUSIONS: Our data show, based on a reasonably large sample, that a pronounced activation of the adrenergic system is not associated with vascular smooth muscle cell hypertrophy or hyperplasia in humans. It is therefore possible that adrenergic mechanisms may have a relevant role in the development of eutrophic remodeling in small vessels.     

Morphometric study of structural changes in the mesenteric blood vessels of spontaneously hypertensive rats

Structural changes of three categories of mesenteric arteries (representing elastic, muscular and arteriolar vessels) from 10- to 12-week-old and 28-week-old spontaneously hypertensive rats (SHR) were studied morphometrically at the light microscope level, and the results compared with age-matched Wistar-Kyoto normotensive rats. In 10- to 12-week-old SHR, hypertrophy of the vessel wall occurred only in the muscular and arteriolar vessels. At 28 weeks, further thickening of the vessel wall occurred in the muscular and arteriolar vessels, and the superior mesenteric artery (elastic vessel) was also thickened in the SHR. There was no evidence that the wall of the relaxed hypertrophied vessels encroached upon the lumen of the vessel. The structural basis for the increase in the vessel wall thickness varied with vessel type. In the superior mesenteric artery, increase in the media at 28 weeks of age would be consistent with hypertrophy of the smooth muscle cells. In the large muscular arteries, at 10-12 weeks of age, increase in medial mass occurred with increase in the number of the smooth muscle cell layers whereas at 28 weeks further increase in media could be due to hypertrophy of the smooth muscle cells. In the small arteriolar vessels, medial enlargement was due at all ages to an increase in the number of smooth muscle layers. Our results show that in the SHR hypertrophy of the media occurs not only in the small arteriolar vessels, but also in large elastic and muscular arteries.     

Cell and wall morphology of intestinal arterioles from 4- to 6- and 17- to 19-week-old Wistar-Kyoto and spontaneously hypertensive rats

To determine whether vascular smooth muscle cells around intestinal arterioles of various sizes undergo comparable changes in spontaneously hypertensive rats, 4- to 6-week-old (n = 10) and 17- to 19-week-old (n = 10) rats from the Wistar-Kyoto and the spontaneously hypertensive strains were used to study the external morphology of vascular smooth muscle cells by scanning electron microscopy and the vessel wall cross-sectional characteristics by light microscopy. At the time of fixation all vascular tone had been abolished. Scanning electron microscopy analysis revealed that all Wistar-Kyoto and spontaneously hypertensive rats at a given age have spindle-shaped vascular smooth muscle cells of comparable length and longitudinal width for a given branching order of arterioles. However, normal maturation is associated with elongation and widening of the vascular smooth muscle cells. Light and scanning electron microscopy indicated that a monolayer of vascular smooth muscle cells, wrapped at almost 0 degree to the vessel's radial axis, is maintained in adult spontaneously hypertensive rats. The radial thickness of this vascular smooth muscle cell monolayer was significantly (p less than 0.025) increased for only the largest arterioles of young and adult spontaneously hypertensive rats. This radial thickening of individual vascular smooth muscle cells increased the muscular component of the wall area for the largest arterioles by about 50% in adult spontaneously hypertensive rats. Other smaller submucosal arterioles of young and adult spontaneously hypertensive rats had normal vessel wall and vascular smooth muscle cell characteristics. These data indicate that hypertrophy in the smooth muscle cell's radial dimension is the primary morphological change in intestinal arterioles of spontaneously hypertensive rats. However, the vascular smooth muscle cell hypertrophy is confined to the largest arterioles such that the remaining smaller arteriolar vessels in the spontaneously hypertensive rat retain a normal smooth muscle cell and overall wall morphology.     

Influence of vascular smooth muscle heterogeneity on angiotensin converting enzyme activity in chicken embryonic aorta and in endothelial cells in culture.

The smooth muscle of the abdominal region of the chicken aorta derives from locally recruited mesenchyme (mesenchymal smooth muscle), whereas that of the thoracic region derives from the neural crest (ectomesenchymal smooth muscle). We hypothesized that this smooth muscle heterogeneity might affect important enzymatic functions of the vessel wall. Therefore, we measured angiotensin converting enzyme (ACE) activity in homogenates of chicken thoracic and abdominal aorta at different embryonic stages (days 10, 14, and 18 of gestation). ACE activity increased in both regions over the time of gestation (p less than 0.001 in both cases); the increase was steeper and ACE activity was higher in thoracic than in abdominal segments (p less than 0.001). Km values were similar (approximately 7 microM) at all times and between the two segments, whereas changes in Vmax values closely paralleled those in enzyme activity, indicating gestation-dependent increases in the amount of enzyme. Neural crest ablation at an early developmental stage resulted in an increase of ACE activity in thoracic homogenates (p less than 0.001), predictably leaving that in abdominal homogenates unaffected. Bovine pulmonary artery endothelial cell monolayers exposed to media conditioned with cultured mesenchymal or ectomesenchymal smooth muscle cells exhibited elevated ACE activity (46% and 83%, respectively, relative to control medium, with p less than 0.01 in both cases; p less than 0.05 between the two media). Increases in endothelial cell ACE activity corresponded to proportional increases in ACE protein determined by enzyme-linked immunosorbent assay (r = 0.99) and were interpreted as indicative of enhanced enzyme synthesis subsequent to exposure of endothelial cells to smooth muscle-conditioned media.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of antihypertensive therapy on hypertensive vascular disease

Hypertension is associated with alterations in the structure, function, and mechanical properties of large and small arteries. Changes in the endothelium, smooth muscle cell, extracellular matrix, and possibly the adventitia, contribute to complications of hypertension. In large arteries, vascular hypertrophy is found, often with increased stiffness of media components. In small arteries, particularly in mild hypertension, rearrangement of smooth muscle cells around a smaller lumen without changes in media volume (eutrophic remodeling) occurs; in more severe hypertension, hypertrophic remodeling with increased vascular stiffness can be found. Vascular remodeling is accompanied by an increase in the extracellular matrix, particularly collagen deposition. Recent studies have demonstrated that vascular remodeling and endothelial dysfunction of small and large vessels may be normalized by treatment with some antihypertensive agents (angiotensin converting enzyme inhibitors, angiotensin AT1 receptor antagonists, and long-acting calcium channel blockers). Angiotensin converting enzyme inhibitors have now been shown to improve outcomes in hypertensive patients, an effect that may in part be related to the vascular protective effects reviewed here.     

Short-term treatment of spontaneously hypertensive rats with liver growth factor reduces carotid artery fibrosis, improves vascular function, and lowers blood pressure

OBJECTIVE: Liver growth factor (LGF), a mitogen for liver cells, reduces fibrosis in a rat model of cirrhosis. The present study assesses the possible vascular antifibrotic and antihypertensive effects of LGF treatment on spontaneously hypertensive rats (SHR). METHODS: Six-month-old male SHR and normotensive Wistar Kyoto rats (WKY) were treated with LGF (4.5 microg LGF/rat i.p. twice a week for 2 weeks). Haemodynamic parameters were measured in anaesthetized rats. Vascular structure and function were studied in carotid arteries using optical and confocal microscopy, radioimmunoassay for desmosine, and isometric tension recording. RESULTS: LGF reduced systolic and diastolic blood pressure only in SHR. When compared to those of untreated SHR, carotid arteries from LGF-treated SHR showed: 1) a 50% reduction in collagen area and an increase in vascular smooth muscle cell number in the media, 2) no difference in total elastin content, but an increase in size of fenestrae in the internal elastic lamina, and 3) enhanced relaxation to acetylcholine, sodium nitroprusside, and forskolin. These effects were specific for SHR, since no changes were observed in LGF-treated WKY. CONCLUSION: Short-term treatment with a low dose of LGF induced a large improvement in vascular structure and function and significantly reduced blood pressure in a rat model of essential hypertension. The present results could open future research to explore the vascular effects of this endogenous factor in order to determine its potential as an antifibrotic and antihypertensive agent in humans.