Arterial Structural Changes Research Articles

Atherosclerosis-induced chronic arterial insufficiency causes clitoral cavernosal fibrosis in the rabbit.

In our previous studies we found that aging-associated fibrosis of clitoral cavernosal tissue correlated with the prevalence of cardiovascular disease in elderly women. The aim of this study was to determine specifically, arterial insufficiency-related structural changes of clitoral cavernosal tissue in a rabbit model. New Zealand white female rabbits were divided into clitoral cavernosal ischemia (CCI, n = 5) and control (n = 5) groups. The CCI group underwent balloon endothelial injury of the iliac arteries and received 0.5% cholesterol diet. The control group received a regular diet. After 16 weeks, arteriography was performed then the animals were sacrificed. The iliac arteries and the entire clitoris were removed. Cross-sections of the iliac arteries and clitoris were processed for histologic evaluation The percentage of smooth muscle and connective tissue in trichrome stained sections of clitoral cavernosal tissue was determined by computer-assisted histomorphometry. Arteriography revealed diffused occlusive disease in the common iliac, internal iliac and pudendal arteries in the CCI group. Histology showed that arterial occlusive disease spreads from the site of balloon injury to the smaller branches involving the clitoral cavernosal arteries. Diffuse fibrosis was observed in the clitoral cross-sections of the CCI group. The percentage of clitoral cavernosal smooth muscle (mean +/- standard error) in the CCI group (53% +/- 0.9%) was significantly decreased compared with the control group (62% +/- 0.8%) (P = 0.0001). Chronic clitoral cavernosal ischemia causes significant fibrosis and loss of smooth muscle in the clitoral cavernosal tissue. These findings suggest that chronic clitoral cavernosal arterial insufficiency may play a role in the pathophysiology of female sexual arousal disorders.

Antenatal dexamethasone enhances endothelin receptorB expression in hypoplastic lung in nitrofen-induced diaphragmatic hernia in rats

Background/Purpose: The hypoplastic lung and persistent pulmonary hypertension (PPH) are the principle causes of high mortality and morbility in infants with congenital diaphragumatic hernia (CDH). Endothelin-1 (ET 1), which is produced by vascular endothelial cells and some leukocytes, plays a key role in modulating pulmonary vascular tone in PPH. Two different receptors (ETA and ETB) for ET-1 have been characterized. Binding of ET-1 to ETA, which is present on smooth muscle cells in fetal lung, results in vasoconstriction. However, binding of ET-1 to ETB which is present on endothelial cells results in vasodilation mediated by endogenous nitric oxide. Antenatal glucocorticoid therapy has been shown to prevent abnormal pulmonary arterial structural changes in animal model with CDH. The aim of this study was to investigate the effect of antenatal glucocorticoid administration on ET-1 system in nitrofen-induced CDH hypoplastic lung in rats.Methods: A CDH model was induced in pregnant rats after administration of nitrofen on day 9.5 of gestation. Dexamethazone (Dex) was given intraperitoneally on days 18.5 and 19.5 of gestation. Cesarean section was performed on day 21 of gestation. Rat ET-1 protein expression was measured in solubilized lung tissue extracts, by sandwich type enzyme-linked immunosorbent assay (ELISA) analysis. Reverse transcription polymerase chain reaction was performed to evaluate the relative amount of ET-1, ET., and ETB mRNA expression.Results: The ET-1 protein and mRNA expression of ET-1 and both receptors were increased significantly in CDH lung compared with controls. Although there was no significant difference in ETA mRNA expression between CDH lung with Dex treatment and without Dex treatment, ETB mRNA expression was elevated significantly in CDH lung with Dex treatment compared with CDH lung without Dex treatment.Conclusion: These findings suggest that antenatal glucocorticoid therapy may modulate pulmonary vascular tone in CDH hypoplastic lung by selectively upregulating local expression of ETB

Ultrasonographic study of carotid artery structural changes with natural longevity.

The changes in carotid artery structure during the natural longevity of the Uighurs people were compared with other ethnic groups. The 419 subjects were divided into (1) longevity and (2) older groups as follows: Uighurs longevity group in Hotan (ULH); and Uighurs, Hans and Kazaks older groups in Hotan or Balikun (UOH, HOH, HOB and KOB). The wall thickness of the common carotid artery (CCA) was measured by ultrasonography. Risk factors were evaluated by measuring total cholesterol (T-C), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG) and fasting glucose, and by 24-h ambulatory blood pressure monitoring. Wall thickness and blood pressure were greater in the Balikun groups than in the Hotan groups. The CCA wall was thicker in Uighurs and Kazaks than in Hans, in the ULH than in the UOH. There was no significant difference in blood pressure among the Hotan groups. LDL-C and glucose were higher and HDL-C was lower in the Hotan groups than in the Balikun groups. T-C, LDL-C, TG and glucose were higher in the HOH than in the ULH and UOH. Systolic blood pressure and LDL-C were higher and TG was lower in the KOB than in the HOB. These results suggest that an increased CCA wall thickness can be attributed to age in Hotan, and to a higher blood pressure level in Balikun, and that the higher blood pressure affected the Balikun groups more than the Hotan groups.

Effects of Extracellular Superoxide Dismutase on Arterial Vascular Structural Changes After Acute Subarachnoid Hemorrhage in the Mouse

P113 Background and Purpose: Subarachnoid hemorrhage (SAH) is a known cause of cerebral vasospasm. Vasopasm may result from loss of endothelial NO synthesis. There is also evidence that Hgb products released after SAH bind NO and deplete its extracellular bioavailability. Cu/Zn superoxide dismutase (SOD) overexpression has been shown to provide protection against vasospasm presumably by reducing available superoxide to react with and deplete NO thereby increasing NO concentration. This study characterized the effects of extracellular SOD (EC-SOD) on vasospasm comparing transgenic EC-SOD overexpressing mice to wild type (WT) counterparts. Methods: Mice underwent halothane anesthesia and endovascular perforation of the right proximal anterior cerebral artery (ACA) using a 5–0 monofilament. Sham mice underwent surgery but no vascular perforation. Temperature, blood gases, & blood pressure were maintained within normal ranges. Three days after recovery, brains were sectioned and Gomori’s trichromic stained. Vascular wall thickness was measured in triplicate sections from the proximal and distal segments of the ACA with the observer blinded to genotype. N=5 per group. Results: There was no difference in wall thickness between EC-SOD overexpressors and wild type shams in either ACA segment (Proximal: EC-SOD = 64±22μm, WT = 72±8μm, p=0.62; Distal: EC-SOD = 77±13μm, WT = 68±9μm, p=0.2). For both genotypes, SAH caused increased wall thickness which was greater in the EC-SOD vs. wild type SAH groups in the proximal (EC-SOD = 164±9μm, WT = 108±27μm, p=0.01) but not distal (EC-SOD =136±37μm, WT = 106±38μm, p=0.28) ACA segments. Conclusions: We were unable to demonstrate amelioration of vasospasm by the five-fold increase of brain EC-SOD known to occur in these mutants. In fact, in the proximal ACA, wall thickness was greater in the EC-SOD overexpressors subjected to SAH. Absence of a beneficial EC-SOD effect might be attributable to the post-SAH measurement interval when processes other than NO metabolism are likely to account for vasospasm. The reason for the pattern of an adverse effect of EC-SOD overexpression is unknown.

Arterial structural changes with verapamil in spontaneously hypertensive rats

Reducing pulse pressure might be more powerful than reducing mean arterial pressure to obtain regression of vascular hypertrophy. However, this hypothesis has never been investigated in the conduit arteries of intact hypertensive animals. A group of 4-week-old spontaneously hypertensive rats (SHR) was treated with the calcium-entry blocker verapamil (50 mg/kg) for 16 weeks and compared with untreated SHR and control Wistar Kyoto (WKY) normotensive rats of the same age. At the end of the experiment, intraarterial thoracic aorta blood pressure was measured both in the conscious and anesthetized animals. Carotid artery diameter and stiffness (echo-tracking techniques) and aortic histomorphometry were determined in parallel. With verapamil, pulse pressure, but not mean arterial pressure, was significantly decreased but did not reach the normotensive values. Carotid internal diameter, medial thickness, and collagen content were significantly reduced by comparison with SHR and did not differ from the values of the WKY group. A significant positive and independent correlation was observed between pulse pressure and medial thickness in the overall population. The study shows that, in SHR chronically treated with verapamil, structural changes may be completely prevented without any change in mean arterial pressure. The parallel change in pulse pressure might suggest that mechanosensitive elements within the vascular wall may be selectively sensitive to the dynamic aspects of physical forces and are able to convert frequency and amplitude information into cellular responses that lead to vascular remodeling.

Administration of antenatal glucocorticoids prevents pulmonary artery structural changes in nitrofen-induced congenital diaphragmatic hernia in rats

Background/Purpose: The aim of this study was to investigate whether maternal administration of dexamethasone has any effect on pulmonary vasculature in nitrofen-induced experimental congenital diaphragmatic hernia (CDH) in a rat model. Methods : A CDH model was induced in pregnant rats after administration of 100 mg nitrofen on day 9.5 of gestation. Antenatal dexamethasone, 0.25 mg/kg was given intraperitoneally on day 18.5 and 19.5 of gestation. The fetuses were divided into three groups: group I (n = 10), normal controls; group II (n = 10), nitrofen-induced CDH; group III (n = 10), nitrofen-induced CDH with maternal antenatal dexamethasone treatment. The fetuses were killed by cesarean section at term. Victorian blue van Gieson staining and immunostaining with antialpha smooth muscle actin (ASMA) were performed on lung tissue. The degree of adventitial thickness and area, and medial thickness and area were measured in pulmonary arteries by image analyzer and analyzed statistically. Results : There was a significant increase in adventitial thickness and area in group II compared with group I and III ( P < .01). There was also a significant increase in medial thickness in group II compared with group I and III ( P < .01). The degree of adventitial thickness and area and degree of medial thickness and area were similar in controls and maternal dexamethasone-treated CDH group. Conclusion : This study demonstrates that antenatal maternal dexamethasone treatment prevents pulmonary artery structural changes in nitrofen-induced CDH in rats.

Age-related deterioration in arterial structure and function in postmenopausal women: impact of hormone replacement therapy.

Epidemiological evidence suggests that hormone replacement therapy (HRT) reduces morbidity and mortality from cardiovascular diseases in postmenopausal women. In this study, indices of arterial function [total systemic arterial compliance (SAC) and carotid arterial distensibility coefficient (DC)], structure [carotid intima-media thickness (IMT)], and lipid profiles were compared in postmenopausal women on long-term HRT and aged-matched controls. One hundred nine women aged 44 to 77 years taking HRT and an age-matched group of 108 female controls were entered into the study. The two groups were similar for body mass index, smoking status, exercise level, alcohol intake, and blood pressure. Fasting cholesterol, low density lipoprotein, and lipoprotein(a) were reduced and high density lipoprotein increased in the HRT group. IMT increased with age; SAC and DC were reduced with age in both groups. The HRT group had a higher mean SAC (0.42+/-0.02 versus 0.34+/-0.02 U/mm Hg, P=0.0001) and a lower mean IMT (0.67+/-0.01 versus 0.74+/-0.02 mm, P=0.006) than did controls. Subgroup analysis for estrogen versus estrogen plus progestin revealed no differences for SAC and IMT; DC, however, was greater in estrogen-only users. Smokers on HRT had a higher mean SAC (0.41+/-0.02 versus 0.31+/-0.01 U/mm Hg, P=0.008) and a lower IMT (0.65+/-0.02 versus 0.75+/-0.03 mm, P=0.002) than did smokers not taking such therapy. A protective effect of long-term estrogen therapy on age-related changes in arterial structure and function in postmenopausal women was evident in smokers and nonsmokers alike. Progestin appeared to counteract the effects of estrogen on carotid compliance only. Long-term controlled trials are needed to determine the significance of these findings.

Effects of a chronic high-salt diet on large artery structure: role of endogenous bradykinin.

Bradykinin activity could explain the blood pressure increase during NaCl loading in hypertensive animals, but its contribution on vascular structure was not evaluated. We determined cardiac mass and large artery structure after a chronic, 4-mo, high-salt diet in combination with bradykinin B2-receptor blockade by Hoe-140. Four-week-old rats were divided into eight groups according to strain [spontaneously hypertensive rats (SHR) vs. Wistar-Kyoto (WKY) rats], diet (0.4 vs. 7% NaCl), and treatment (Hoe-140 vs. placebo). In WKY rats, a high-salt diet significantly increased intra-arterial blood pressure with minor changes in arterial structure independently of Hoe-140. In SHR, blood pressure remained stable but 1) the high-salt diet was significantly associated with cardiovascular hypertrophy and increased arterial elastin and collagen, and 2) Hoe-140 alone induced carotid hypertrophy. A high-salt diet plus Hoe-140 acted synergistically on carotid hypertrophy and elastin content in SHR, suggesting that the role of endogenous bradykinin on arterial structure was amplified in the presence of a high-salt diet.

Regular walking increases peak limb vasodilatory capacity of older hypertensive humans: implications for arterial structure.

Although regular aerobic exercise has been shown to lower arterial blood pressure in older adult humans with essential hypertension, the mechanisms responsible for this hypotensive effect remain largely unknown. To examine the hypothesis that the reduction in arterial blood pressure in older hypertensive humans with regular exercise is accompanied by evidence of a change in arterial structure. We measured peak limb vascular conductance, a well-established noninvasive measure of arterial structure, both in the forearm (untrained limb) and in the calf (exercise-trained limb) of 22 older adults (aged 51-74 years) with stage 1 or 2 essential hypertension. Eleven subjects walked 3-4 days/week at a mild exercise intensity (45% of heart rate reserve) for 6 months. Eleven other subjects served as nonexercising controls. Maximal oxygen consumption of subjects in the exercise group increased by 17% (P < 0.05) with no change in body mass and body fat. Systolic and diastolic arterial blood pressures at rest were reduced by 7 +/- 4 and 5 +/- 2 mmHg, respectively (P < 0.05). There were roughly 20% increases in peak forearm blood flow and peak forearm vascular conductance (both P < 0.05). Similar increases in peak calf blood flow and vascular conductance were observed (both P < 0.01). There were no significant changes in any of these variables over the same time period for the nonexercising controls. The decrease in resting blood pressure in older adults with stage 1 or 2 essential hypertension in response to regular aerobic exercise is associated with an increase in peak limb vascular conductance, which could be due in part to favorable changes in arterial structure. These exercise-induced functional and, possibly, structural changes are not confined to the exercise-trained limbs, but rather are more systemic in nature. These apparent beneficial changes in limb vasodilatory capacity and vascular structure can be produced with a mode, intensity, and frequency of aerobic exercise that can be tolerated and is commonly performed by older adults.

Effect of Antihypertensive Treatment on Cardiac and Subcutaneous Artery Structure: A Comparison Between Calcium Channel Blocker and Thiazide-Based Regimens

The effects of two antihypertensive regimens (isradipine and hydrochlorothiazide-amiloride) on the ratio between media thickness and lumen diameter of subcutaneous arteries and on left ventricular mass in essential hypertension were compared. Fifty patients, aged 46.3 ± 8 (mean ± SD) years, with newly diagnosed or poorly controlled essential hypertension were randomized to treatment with either isradipine or hydrochlorothiazide-amiloride. Atenolol and hydralazine were added in both groups as secondary and tertiary drugs, respectively, when needed for normalization of diastolic blood pressure. A subcutaneous gluteal biopsy was taken surgically before medication and again after 9 months of successful antihypertensive treatment. Two small resistance arteries were isolated from each biopsy and mounted in a Mulvany-Halpern isometric small vessel myograph. The media thickness-to-lumen diameter ratio (percentage) of the vessels was measured under standardized conditions and meaned. Left ventricular mass (LVM) index was determined by echocardiography according to the Penn convention. Ten patients were treated with isradipine as monotherapy, whereas only one patient was well controlled on diuretics as monotherapy. Mean blood pressure was reduced equally with the two regimens, from 131 ± 9 mm Hg to 101 ± 10 mm Hg with the isradipine and from 128 ± 9 mm Hg to 99 ± 7 mm Hg with the thiazide/atenolol regimen. LVM decreased significantly in both groups by 130 ± 75 g with the isradipine-based regimen and by 70 ± 53 g with the hydrochlorothiazide/atenolol-based regimen. The reduction of LVM was significantly greater on the isradipine-based regimen than on the thiazide-based regimen ( P < .01). There was a significant reduction of media thickness-to-lumen diameter ratio during treatment with the isradipine-based regimen from 10.9% to 8.8% ( P < .01). The reduction in the thiazide regimen was from 9.7% to 8.5%, which was not significant ( P = .07). The study demonstrated significant reduction of hypertensive changes in peripheral resistance artery structure during antihypertensive treatment with an isradipine-based regimen. The thiazide/β-blocker-based regimen did not have a significant effect on the vessels. Significant reduction of LVM was achieved with both isradipine-based and thiazide/atenolol-based regimens. The reduction of LVM obtained with the isradipine-based regimen was significantly greater than that of the thiazide/atenolol-based regimen.

Arterial Disease in Dipper and Nondipper Hypertensive Patients

Carotid artery and small vessel structural changes were evaluated in 45 dipper and 45 nondipper hypertensive subjects matched for sex, age, body mass index, smoking habit, and serum lipids. Patients underwent carotid ultrasonography to evaluate lumen diameter, intima-media thickness, cross-sectional area, and atherosclerotic plaques, and plethysmographic examination to record minimum forearm vascular resistance. In the whole study population, carotid cross-sectional area and prevalence of atherosclerotic plaques tended to be higher in nondippers than in dippers (19.9 +/- 6.0 v 17.5 +/- 6.1 mm2, P = .07, and 40% v 26%, P = .18), whereas intima-media thickness and minimum forearm vascular resistance were significantly higher in nondippers than in dippers (0.89 +/- 0.12 v 0.8 +/- 0.15 mm, P < .02, and 2.53 +/- 0.3 v 2.34 +/- 0.3 arbitrary resistance units (RU), P < .02). When gender was taken into account, different results were obtained in men and women. In men, vascular characteristics were not significantly different between dippers and nondippers. In women, carotid cross-sectional area and prevalence of atherosclerotic plaques tended to be higher in nondippers than in dippers (18.3 +/- 4.9 v 15.5 +/- 4.5 mm2, P = .06, and 40% v 15%, P = .15), and intima-media thickness and minimum forearm vascular resistance were significantly higher in nondippers than in dippers both before (0.84 +/- 0.1 v 0.73 +/- 0.1 mm, P < .01, and 2.38 +/- 0.3 v 2.16 +/- 0.2 RU, P < .01) and after adjustment for 24-h blood pressure. In conclusion, our data suggest that the progression of vascular disease may be differently affected in the two sexes by a different circadian blood pressure profile.

Sodium, survival, and the mechanical properties of the carotid artery in stroke-prone hypertensive rats.

Reduction in sodium intake improves the survival of stroke-prone spontaneously hypertensive rats (SHR-SP) without causing any change in their blood pressure. To investigate whether the diuretic indapamide improves survival of SHR-SP and whether changes in the structure and the function of large arteries are associated with survival. Forty-eight hypertensive rats aged 6 weeks were divided into three groups: a control SHR-SP group (n = 24) and a control spontaneously hypertensive rat (SHR) group (n = 12), with 1% saline drinking water; and an indapamide-treated SHR-SP group (n = 12) with 1% saline drinking water administered 1 mg/kg per day indapamide via their food. At the end of a 12-week follow-up period, pulsatile changes in blood pressure and common carotid artery diameter (measured by high-resolution echo-tracking techniques) were determined and aortic histomorphometry was performed. By the end of the study 58% of the SHR-SP control group rats had died. There were no deaths in the other two groups. In these two groups the mean blood pressure (217+/-10 and 212+/-7 mmHg), carotid diameter and distensibility (0.48+/-0.09 and 0.61+/-0.22 mmHg[-1]), arterial thickness (116+/-4 and 116+/-3 microm), and collagen content of the arterial wall were identical. In the SHR-SP control group the mean blood pressure was significantly lower (168+/-9 mmHg), the carotid distensibility was higher (1.47+/-0.35 mmHg[-1]), and the arterial thickness (138+/-5 microm) and collagen content were substantially higher than those in the other two groups. In the study population as a whole, for a given mean arterial pressure the carotid distensibility was identical in the three groups, although the arterial thickness was substantially greater in the SHR-SP control group rats. The study provides evidence that the diuretic compound indapamide improved the survival of SRH-SP even though their blood pressure was higher than that of untreated animals, and that genetic sensitivity to sodium, rather than blood pressure, influences the changes in arterial structure.

Pulmonary artery structural changes in pulmonary hypertension complicating congenital diaphragmatic hernia

Primary pulmonary hypertension is characterized by the presence of smooth muscle cells in nonmuscular compartments or segments of the vessel and the abnormal deposition of collagen in both the small muscular arteries and arterioles and the large elastic arteries. Victorian blue van Gieson staining and immunostaining with anti-alpha smooth muscle actin (ASMA) were performed on lung tissues obtained during autopsy from 21 patients who had congenital diaphragmatic hernia (CDH) complicated by persistent pulmonary hypertension (PPH) and 10 control patients who died of sudden infant death syndrome (SIDS). The degree of medial thickening and adventitial thickening was measured in pulmonary arteries by image analysis and compared statistically. There was a significant increase in adventitial as well as medial thickness in arteries of all sizes in CDH patients compared with control patients ( P < .001). The most striking increase occurred in arteries with an external diameter (ED) of less than 75 μm. Calculation of the areas of the various components in the wall of each vessel showed that for smaller vessels (< 75 μm ED), the area of the lumen was smaller and the area of the media and adventitia was larger in CDH patients compared with control patients ( P < .001). In vessels greater than 75 μ ED, the areas of media in CDH was the same as in controls and the area of adventitia in CDH was significantly larger than controls ( P < .001). The present study provides evidence that an increase in adventitial thickness and adventitial area occurs in pulmonary arteries in CDH patients complicated by PPH. The structural changes in the adventitia of the pulmonary arteries may be an important factor in the development of PPH in patients with CDH.

Hypertension and peripheral arterial disease: a plethysmographic study.

Sixty patients suffering from arterial hypertension and/or obliterative arteriopathy of the lower limbs (20 hypertensive uncomplicated [H group], 20 normotensive affected by obliterative arteriopathy [A group], 20 suffering from both hypertension and peripheral arterial disease [HA group]) were studied, by strain gauge plethysmography, in comparison with 20 healthy subjects (N group). The aims were to evaluate the arterial and venous hemodynamics of the lower limbs in such conditions and also to determine whether the vascular damage is primary or represents a consequence of the hypertensive pathology in the patients affected by both hypertension and peripheral arterial disease. The resting blood flow did not show significant differences in the mean values, even if lightly decreased in hypertensive patients (with or without peripheral arteriopathy). The peak flow was reduced significantly both in the H group and in the A and HA groups. The half-time (t1/2) and total time (tT), which indicate vascular reactivity, were significantly decreased in the H group, but they were increased in the A and HA groups. Finally, the venous compliance was decreased in the H group, did not vary significantly in the A group, and showed an intermediate behavior in the HA group. These results suggest that hypertensive and arteriopathic patients develop similar arterial structural changes. However, they show a different behavior with regard to vascular reactivity and venous hemodynamics, as demonstrated by venous plethysmography.

Arterial wall remodelling and stiffness in hypertension: heterogeneous aspects.

1. Hypertension is associated with hypertrophy and decreased operating distensibility of the large artery wall. Because similar pathological and functional changes are observed with ageing, hypertension is often looked upon as an accelerated form of aging. 2. Considering the decrease in arterial distensibility observed with both ageing and hypertension, whether the change is due to age, an increase in distending pressure or to hypertension-induced changes in large artery structural properties may be much debated. 3. The purpose of the present review is to study the effects of aging and hypertension on structural (lumen diameter and arterial wall thickness) and functional (distensibility) properties of large central and medium-sized arteries in humans. 4. From clinical studies in subjects with hypertension with or without advanced renal disease, it is suggested that age- and hypertension-induced structural arterial changes are quite heterogeneous, depending on the topography of the vessel and on the severity of the underlying disease.

Echographic assessment of carotid and femoral arterial structure in men with essential hypertension. Group PCVMETRA.

Extracoronary in vivo structural arterial changes were studied in asymptomatic essential hypertension. Carotid and femoral arteries were examined with B-mode echography for the presence or absence of plaque (the whole vascular segments of each vessel in the both sides) and for automated measurement of the far wall intima-media thickness (the vascular segment of each vessel proximal to the bifurcation in the right side) in 53 never treated hypertensive men and 133 normotensive men similar with regard to age, serum cholesterol levels, and smoking history. In the hypertensive group carotid plaque was more frequent (P < .05) and carotid and femoral intima-media thicknesses were greater (P < .001) than in the normotensive group. In the overall normotensive and hypertensive population intima-media thickness was independently associated with age and systolic pressure in both arteries (P < .001) and with cholesterol in the femoral artery (P < .05) while plaque was associated with systolic pressure (P < .01), and cholesterol (P < .01) in the carotid arteries and with age (P < .01), cholesterol (P < .05), and smoking (P < .001) in the femoral arteries. No significant difference in intima-media thickness in both arteries existed between hypertensive subjects with plaque and those without. Wall thickening and plaque were more frequent in hypertensive patients. Thickening was distributed homogeneously to both arteries, while plaque affected preferentially the femoral bed. The influence of age and pressure was more marked on intima-media thickness than on plaque. The lack of association between wall thickening and plaque suggested that vascular hypertrophy and early atherosis might be two different structural changes.

Regulation and failure of coronary circulation.

Endothelial driving factors pathophysiologically affect the regulation of coronary circulation. To investigate the regulation of vascular function by endothelium-derived relaxing factor (EDRF) and endothelial cells, endothelium-dependent relaxation impairment was studied in acute ischemia-reperfusion injury in large coronary artery and coronary microvasculature. EDRF (NO) production and release were inhibited due to ischemia-reperfusion injury to the endothelium of large coronary arteries. There was an increased sensitivity selective to ET-1 in large coronary arteries exposed to ischemia and reperfusion. Reduced endothelium-dependent relaxation and augmented ET-1 sensitivity in large coronary arteries suggest the existence of spasmogeneity in reperfused blood vessels. Ischemia and reperfusion also brought about various morphological and functional changes in the reperfused coronary microvasculature. Edema of perivascular interstitium and endothelial cells was the main observation and caused a decrease in the ability of the microvascular bed to dilate because of extravascular compression. To examine the long-term suppression of NO synthesis accompanying endothelial dysfunction, the long-term reactions of coronary arteries and myocardium due to chronic inhibition of NO synthesis by continuously infused L-NAME was investigated. Endothelial cell impairment, proliferation and disarrangement of medial smooth muscle cells, microvascular injury due to platelet thrombi and increased perivascular fibrous tissue were found in rat coronary arteries. Myocardial fibrosis due to coronary microvascular injury was observed. These changes in coronary arterial and myocardial structure were suppressed by ACE inhibitors. Therefore, ACE inhibitors are useful in the treatment of coronary microvascular impairments.

Stratification of vascular risk in hypertension and therapeutic perspective

Hypertension is a major risk factor for cardiovascular disease and atherosclerosis is the cause of most hypertensive complications. Therefore the detection of preclinical atherosclerosis may contribute to the better identification of hypertensive subjects at high risk of complications. Three main alterations are currently able to be diagnosed noninvasively: calcification, thickening, and stiffening of the arterial walls. Calcification of epicardial coronary arteries can be seen noninvasively by ultrafast computed tomography thanks to its rapid acquisition of image. Coronary calcification of epicardial coronary arteries can be seen noninvasively by ultrafast computed tomography thanks to its rapid acquisition of image. Coronary calcification is typical of atherosclerosis but not of stenosis. Conversely, the absence of calcification eliminates, practically, coronary artery disease as a diagnosis. Coronary calcification is present in only 63% of asymptomatic hypertensive men, suggesting that the degree of coronary atherosclerosis associated with high blood pressure varies among individuals. Wall thickening can be quantified in vivo by automated computerized analysis of ultrasonic images of the far wall intima-media complex of extracoronary vessels. Carotid and femoral wall thickening was observed in hypertensive subjects who had never been treated for hypertension compared to normotensive controls of similar age. Such vascular hypertrophy was not found in all patients, attesting to the disparity of the structural arterial changes within hypertensive subjects. Recent evidence from studies of essential hypertension suggests the lack of association between diffuse wall thickening of carotid or femoral arteries and the presence of atherosclerotic plaque (focal echogenic encroachment) in the same vessel. However, other studies in at-risk subjects suggest that extracoronary wall thickening could be related to the presence of coronary atherosclerosis, and to the incidence of coronary events. Wall stiffening is the third arterial alteration related to the sclerotic component of atherosclerosis. Its evaluation is based on the velocity of pulse wave propagation within the arterial tree or on the ultrasonic (echotracking) assessment of arterial wall distension during the cardiac cycle. Arterial stiffening is increased in the presence of hypertension, and such an increase is potentiated by the presence of other risk factors, such as smoking or hypercholesterolemia. Finally, the detection of early atherosclerosis with the above techniques optimizes the stratification of atherosclerotic risk, and may provide relevant information on comparative effectiveness of various classes of antihypertensive agents.

Regional Heterogeneity of Arterial Structural Changes

Arterial structural changes in experimental models of hypertension and restenosis differ between vessel types and within vessels. Inspired by the diversity of short-term functional responses to vasoactive agents, hypotheses are presented with respect to the heterogeneity of structural alterations. Considered are the multifactorial nature of smooth muscle cell growth control and the possibility that vascular smooth muscle is not homogeneous but composed of different smooth muscle cell populations. These hypotheses may help explain the origin of both intervascular and intravascular heterogeneity of vascular structural responses.

Continuous nitric oxide inhalation reduces pulmonary arterial structural changes, right ventricular hypertrophy, and growth retardation in the hypoxic newborn rat.

Breathing low oxygen levels for several weeks produces progressive pulmonary artery hypertension and smooth muscle hypertrophy and hyperplasia in many species. Because nitric oxide (NO) is an important regulator of pulmonary vascular tone, we examined whether the continuous inhalation of low levels of NO gas would attenuate pulmonary arterial structural changes in hypoxic rat pups. Nine-day-old rat pups and their mothers continuously breathed at FIO2 0.21 or 0.10 with or without adding 20 ppm (by volume) NO for 2 weeks. Lung tissue was obtained for vascular morphometric analysis, and the hearts were dissected to measure right ventricular weight and levels of mRNA encoding rat atrial natriuretic factor (rANF). In addition, femur and skull length were radiographically determined. Breathing at FIO2 0.10 for 14 days increased pulmonary arterial wall thickness and the proportion of muscular arteries in the lung periphery. Right ventricular weight and right ventricular rANF gene expression increased, whereas body weight and skeletal growth were reduced (all P < .05). Continuous inhalation of 20 ppm NO at FIO2 0.10 for 2 weeks decreased hypoxic pulmonary vascular structural changes and somatic growth retardation and prevented the increase of right ventricular weight and right ventricular rANF mRNA levels. These observations suggest that chronically breathing NO attenuates pulmonary vascular smooth muscle hypertrophy and/or hyperplasia and extension into distal arterial walls, right ventricular hypertrophy, and growth retardation of newborns breathing at a low oxygen level.