Blood filterability in ischemic heart disease

The aim of this paper is to test whether an alteration of blood flow in microcirculation and in particular of red cell deformability is present in myocardial ischaemia. To this end we determined by the method proposed by Reid and Dormandy (J. Clin. Pharmacol. 1976, 29, 855) whole-blood filterability in 23 patients with myocardial ischaemia, in 15 clinically healthy subjects and in 99 subjects without clinical evidence of ischemic pathology displaying one or more vascular risk factors. Blood filterability turned out to be significantly lower in cases of coronary diseases than in controls (p less than 0,001), while it was lower but not significantly so, than in subjects displaying risk factors. We conclude therefore that the presence of risk factors is enough important to be considered one of the fundamental elements (though non the only one) in causing the reduction of blood-filterability encountered in ischemic cardiopathology.     

Blood filterability in cerebral vascular disease

The aim of this paper is to test whether an alteration of blood flow in microcirculation and in particular of red cell deformability is present in cerebrovascular insufficiency. To this end we determined by the method proposed by Reid and Dormandy (J. Clin. Pharmacol. 1976, 29, 855) whole-blood filterability in 31 patients with cerebrovascular disease, in 15 clinically healthy subjects and in 99 subjects without clinical evidence of ischemic pathology displaying one or more vascular risk factors. Blood filterability turned out to be significantly lower in cases of cerebrovascular disease than in the controls (p less than 0,001), while data about presence of risk factors in cerebrovascular insufficiency and in controls are almost overlapping. Reduction of blood filterability in cerebrovascular disease may therefore be attributed directly to the risk factors associated to the disease, which can significantly reduce red cell deformability. Further we didn't find any significant correlation between blood filterability and levels of fibrinogen, platelets, triglycerides and cholesterol in blood.     

Increased vascular resistance in paralyzed legs after spinal cord injury is reversible by training.

The purpose of the present study was to determine the effect of a spinal cord injury (SCI) on resting vascular resistance in paralyzed legs in humans. To accomplish this goal, we measured blood pressure and resting flow above and below the lesion (by using venous occlusion plethysmography) in 11 patients with SCI and in 10 healthy controls (C). Relative vascular resistance was calculated as mean arterial pressure in millimeters of mercury divided by the arterial blood flow in milliliters per minute per 100 milliliters of tissue. Arterial blood flow in the sympathetically deprived and paralyzed legs of SCI was significantly lower than leg blood flow in C. Because mean arterial pressure showed no differences between both groups, leg vascular resistance in SCI was significantly higher than in C. Within the SCI group, arterial blood flow was significantly higher and vascular resistance significantly lower in the arms than in the legs. To distinguish between the effect of loss of central neural control vs. deconditioning, a group of nine SCI patients was trained for 6 wk and showed a 30% increase in leg blood flow with unchanged blood pressure levels, indicating a marked reduction in vascular resistance. In conclusion, vascular resistance is increased in the paralyzed legs of individuals with SCI and is reversible by training.     

Impaired cerebral autoregulation in obstructive sleep apnea

Obstructive sleep apnea (OSA) increases the risk of stroke independent of known vascular and metabolic risk factors. Although patients with OSA have higher prevalence of hypertension and evidence of hypercoagulability, the mechanism of this increased risk is unknown. Obstructive apnea events are associated with surges in blood pressure, hypercapnia, and fluctuations in cerebral blood flow. These perturbations can adversely affect the cerebral circulation. We hypothesized that patients with OSA have impaired cerebral autoregulation, which may contribute to the increased risk of cerebral ischemia and stroke. We examined cerebral autoregulation in patients with and without OSA by measuring cerebral artery blood flow velocity (CBFV) by using transcranial Doppler ultrasound and arterial blood pressure using finger pulse photoplethysmography during orthostatic hypotension and recovery as well as during 5% CO(2) inhalation. Cerebral vascular conductance and reactivity were determined. Forty-eight subjects, 26 controls (age 41.0+/-2.3 yr) and 22 OSA (age 46.8+/-2.3 yr) free of cerebrovascular and active coronary artery disease participated in this study. OSA patients had a mean apnea-hypopnea index of 78.4+/-7.1 vs. 1.8+/-0.3 events/h in controls. The oxygen saturation during sleep was significantly lower in the OSA group (78+/-2%) vs. 91+/-1% in controls. The dynamic vascular analysis showed mean CBFV was significantly lower in OSA patients compared with controls (48+/-3 vs. 55+/-2 cm/s; P <0.05, respectively). The OSA group had a lower rate of recovery of cerebrovascular conductance for a given drop in blood pressure compared with controls (0.06+/-0.02 vs. 0.20+/-0.06 cm.s(-2).mmHg(-1); P <0.05). There was no difference in cerebrovascular vasodilatation in response to CO(2). The findings showed that patients with OSA have decreased CBFV at baseline and delayed cerebrovascular compensatory response to changes in blood pressure but not to CO(2). These perturbations may increase the risk of cerebral ischemia during obstructive apnea.     

Dysfunction of soluble guanylyl cyclase in aorta and kidney of Goto-Kakizaki rats: influence of age and diabetic state.

Type 2 diabetes mellitus is frequently associated with arterial hypertension. The mechanisms involved in this association are not known in detail, but endothelial dysfunction and a blunted vascular response to endogenous vasodilators are thought to play a role. In the present study we investigated the in vitro activity of vascular and renal soluble guanylyl cyclase in type 2 diabetic Goto-Kakizaki rats aged 5, 15, and 30 weeks, in comparison with age-matched Wistar controls. Blood pressure was monitored by radiotelemetry, and serum glucose and insulin concentrations were measured by standard assays. Goto-Kakizaki rats of all age groups had serum glucose concentrations significantly higher than those of corresponding Wistar controls. Serum insulin was unchanged until 15 weeks of age and was elevated in the 30-week-old diabetic rats. Blood pressure in Goto-Kakizaki rats was significantly higher than that in Wistar controls, and heart rate was significantly lower. Mesenteric arteries of diabetic rats showed a blunted relaxation in response to acetylcholine and sodium nitroprusside. In aortic tissue from Wistar rats an age-dependent increase was found in nitric oxide-stimulated cGMP formation, which was absent in the diabetic animals. Moreover, the maximum activity of soluble guanylyl cyclase was significantly lower in Goto-Kakizaki rats in all age groups studied. In renal tissue no differences were found between diabetic and control rats, except at 30 weeks of age when Goto-Kakizaki rats showed a significant reduction in basal and stimulated guanylyl cyclase activity. In conclusion, the present study shows a persistent reduction in vascular nitric oxide-sensitive guanylyl cyclase in Goto-Kakizaki rats, which occurred shortly after weaning and may contribute to the elevation in blood pressure in this strain of genetically diabetic rats.     

Increased vasoconstrictor sensitivity in obstructive sleep apnea.

We studied vasoconstrictor sensitivity and cholinergic responsiveness of the forearm vasculature in 10 male patients with obstructive sleep apnea (OSA) and 10 healthy controls. Subjects with regular medication, known arterial hypertension, diabetes mellitus, or dyslipidemia were not included in this study. Age, body mass index, blood pressure, blood glucose, serum lipids, and baseline forearm vascular conductance (derived from venous occlusion plethysmography and intra-arterial blood pressure measurement) did not differ significantly between these two groups. With use of three dosage steps each, angiotensin II and acetylcholine were successively infused into the brachial artery. During infusion of angiotensin II, mean conductance was 39.6% lower (P = 0.002) in the OSA patients compared with that in the control subjects. Vascular responsiveness to increasing dosages of acetylcholine was not significantly altered in the OSA group. These findings suggest an enhanced vasoconstrictor sensitivity in the forearm vasculature in OSA. The hypothesis that endothelial function in OSA is impaired independently of other cardiovascular risk factors is not supported by the present results.     

Blood Coagulation and Platelet Economy in Subjects with Primary Gout

Previous studies have suggested that there is an increased incidence of degenerative vascular disease in patients with gout and an increased rate of turnover of blood platelets in patients and animals with atherosclerosis. A disturbed uric acid metabolism and “secondary” gout have long been known to occur with bone marrow diseases. A study of platelet economy and blood clotting factors in subjects with primary gout was therefore undertaken.Twenty-two male subjects with gout but with no clinical evidence of vascular disease were studied. Half of these had a negative family history for vascular disease and half had less fortunate ancestors. The most striking differences were found when gouty patients with a negative family history for vascular disease were compared with similar control subjects. The mean platelet half-life was 2.85 days in the gouty subjects and 3.74 days in the controls. The mean platelet turnover (number/c.mm./day) was 58,750 in gouty subjects, 42,370 in controls. Platelet adhesiveness and plasma thromboplastic activity were correspondingly increased in the gouty subjects. Control subjects with a positive family history all showed relatively active clotting system and platelet turnover, similar to the values found in atherosclerotic subjects. The data indicated that there is increased platelet destruction and production in some patients with primary gout. The relation between this anomaly and the vascular disease, and disturbed urate metabolism in gouty subjects, remains to be investigated.     

Effect of different prostaglandin synthesis inhibitors on post-occlusive blood flow in human forearm

The vascular relaxation response in the human forearm that follows a short period of arterial occlusion (reactive hyperemia) was investigated with respect to its dependance on an intact PG synthesis. In 10 healthy subjects, five men and five women, forearm blood flow was measured, using venous occlusion plethysmography, in the basal state and during the recovery phase following 5 min of obstructed arterial flow. The subjects were studied at nine different occasions. At six of these they were pre-treated with the highest recommended doses of either of the PG synthesis inhibitors acetyl-salicylic acid, diclofenac, ibuprofen, indomethacin, naproxen or piroxicam; the remaining occasions were controls, performed in the absence of drugs in the beginning, middle, and end of the series.All the drugs significantly decreased the total reactive hyperemia following 5 min of arterial occlusion. Ibuprofen was the most efficient agent, inhibiting the total reactive hyperemia by more than 70%, and naproxen was least active, producing about 35% inhibition. The rest of the drugs diminished the total reactive hyperemia by 55–65%. Basal forearm blood flow was not affected by either of the agents.From these data we conclude that drugs which inhibit PG synthesis in man have in common the capacity to decrease post-occlusive reactive hyperemia. This indicates that an activation of the local release of arachidonic acid, leading to formation of vasodilator PG, is one of the main factors behind the vascular smooth muscle relaxation response to arterial occlusion.     

Arterial wall-determined risk factors to vascular diseases

Many decades of research have led to considerable in-depth understanding of circulating factors that may lead to coronary atherosclerosis. However, not every individual with serious known risk factors such as hypercholesterolemia or cigarette smoking develops atherosclerosis. Differential susceptibility of the arterial wall to circulating atherogenic risk factors, which may be largely controlled by genetic variants, may provide this missing link. Endothelial cells, the lining of the arterial wall, are responsible for the integrity and responses to the circulating environment. Dysfunctional endothelial cells and the subsequent proliferation of vascular smooth muscle cells are the prelude of atherosclerosis and acute coronary syndrome. Yet, there have been no detailed studies exploring the interaction between circulating environmental and arterial wall endogenous risk factors in living human subjects. This deficiency is largely the result of restricted access. Genetic factors almost certainly play a key role in directing how the arterial wall responds to circulating "environmental" factors. This endogenous-exogenous (i.e. the arterial wall-circulating) blood balance is the reflection of nature-nurture or gene-environment interaction. Understanding the interaction fully will require direct access to the arteries, and nonhuman primates can provide an excellent model for such investigations. In the current review, we discuss the importance of arterial wall factors in vascular diseases and present a baboon model for practical studies of arterial wall factors and their interaction with circulating factors. Direct biopsy access to baboon arteries will provide a unique opportunity to explore arterial wall susceptibilities and to evaluate the direct effects of diet or pharmaceutical agents on vascular diseases. The use of baboons from large pedigreed families in these studies will enable the identification of genes that interact with these environmental factors in determining individual risk of atherosclerosis.     

The age factor in blood flow in the calf and in vascular resistance at rest and in reactive hyperaemia.

The blood flow and vascular resistance in the calf were studied in two groups of healthy subjects (mean ages 22 and 49 years) at rest and in reactive hyperaemia produced by five minutes' ischaemia of the lower limb. The blood flow was determined by venous occlusive plethysmography and vascular resistance was computed from the mean blood pressure measured by auscultation on the arm and from the blood flow in the calf, at rest and during reactive hyperaemia. The resting flow and blood flows throughout practically the whole time of hyperaemia were found to be significantly smaller in young individuals. The maximal flow was significantly lower, the maximal flow time was significantly prolonged in young subjects. The recovery time and repayment of the flow debt in the two groups were the same. Vascular resistance in the calf was significantly greater in young subjects, both at rest and during dilatation. We assume from the results that the capacity of the arterial system in the lower limbs is significantly smaller in young individuals.     

Early effects of tobacco smoke exposure on vascular dynamics in the microcirculation.

The purpose of these studies is to examine the early effects of chronic tobacco smoke exposure on vascular dynamics in the mesenteric microcirculation. Female rats were exposed daily to tobacco smoke from five reference cigarettes for a period of 2 mo. At the end of this period the smoke-treated rats had gained 12 g less than sham-treated controls, and arterial blood pressure in the smoke-treated animals was slightly less than pressure in the sham-treated animals. These are characteristic effects of tobacco smoke exposure on rats. Following the treatment period, red blood cell (RBC) velocity in single mesenteric capillaries and microvascular pressures in arterioles and venules were measured in accordance to established methods. There was no significant difference in pressure distribution on the arterial side of the mesenteric vascular network, but pressure in the venules of the smoke-treated animals was significantly higher than that of the sham-treated group. In association with the higher venular pressure in the smoke-treated animals, capillary RBC velocity (an index of capillary flow) was significantly lower. The reduction in velocity was in proportion to the decrease in pressure drop (arteriole-venule) across the capillary network.     

Respiratory, circulatory and neuropsychological responses to acute hypoxia in acclimatized and non-acclimatized subjects

Respiratory, circulatory and neuropsychological responses to stepwise, acute exposure at rest to simulated altitude (6,000 m) were compared in ten acclimatized recumbent mountaineers 24 days, SD 11 after descending from Himalayan altitudes of at least 4,000 m with those found in ten non-acclimatized recumbent volunteers. The results showed that hypoxic hyperpnoea and O2 consumption at high altitudes were significantly lower in the mountaineers, their alveolar gases being, however, similar to those of the control group. In the acclimatized subjects the activation of the cardiovascular system was less marked, systolic blood pressure, pulse pressure, heart rate and thus (calculated) cardiac output being always lower than in the controls; diastolic blood pressure and peripheral vascular resistance, however, were maintained throughout in contrast to the vasomotor depression induced by central hypoxia which occurred in the non-acclimatized subjects at and above 4,000 m [alveolar partial pressure of O2 less than 55-50 mmHg (7.3-6.6 kPa)]. It was concluded that in the acclimatized subjects at high altitude arterial vasodilatation and neurobehavioural impairment, which in the non-acclimatized subjects reflect hypoxia of the central nervous system, were prevented; that acclimatization to high altitude resulted in a significant improvement of respiratory efficiency and cardiac economy, and that maintaining diastolic blood pressure (arterial resistance) at and above 4,000 m may represent a useful criterion for assessing hypoxia acclimatization.     

Strength training reduces arterial blood pressure but not sympathetic neural activity in young normotensive subjects.

The effects of resistance training on arterial blood pressure and muscle sympathetic nerve activity (MSNA) at rest have not been established. Although endurance training is commonly recommended to lower arterial blood pressure, it is not known whether similar adaptations occur with resistance training. Therefore, we tested the hypothesis that whole body resistance training reduces arterial blood pressure at rest, with concomitant reductions in MSNA. Twelve young [21 +/- 0.3 (SE) yr] subjects underwent a program of whole body resistance training 3 days/wk for 8 wk. Resting arterial blood pressure (n = 12; automated sphygmomanometer) and MSNA (n = 8; peroneal nerve microneurography) were measured during a 5-min period of supine rest before and after exercise training. Thirteen additional young (21 +/- 0.8 yr) subjects served as controls. Resistance training significantly increased one-repetition maximum values in all trained muscle groups (P < 0.001), and it significantly decreased systolic (130 +/- 3 to 121 +/- 2 mmHg; P = 0.01), diastolic (69 +/- 3 to 61 +/- 2 mmHg; P = 0.04), and mean (89 +/- 2 to 81 +/- 2 mmHg; P = 0.01) arterial blood pressures at rest. Resistance training did not affect MSNA or heart rate. Arterial blood pressures and MSNA were unchanged, but heart rate increased after 8 wk of relative inactivity for subjects in the control group (61 +/- 2 to 67 +/- 3 beats/min; P = 0.01). These results indicate that whole body resistance exercise training might decrease the risk for development of cardiovascular disease by lowering arterial blood pressure but that reductions of pressure are not coupled to resistance exercise-induced decreases of sympathetic tone.     

The Contribution of Arterial Calcification to Peripheral Arterial Disease in Pseudoxanthoma Elasticum

Background and aims

The contribution of arterial calcification (AC) in peripheral arterial disease (PAD) and arterial wall compressibility is a matter of debate. Pseudoxanthoma elasticum (PXE), an inherited metabolic disease due to ABCC6 gene mutations, combines elastic fiber fragmentation and calcification in various soft tissues including the arterial wall. Since AC is associated with PAD, a frequent complication of PXE, we sought to determine the role of AC in PAD and arterial wall compressibility in this group of patients.

Methods and Results

Arterial compressibility and patency were determined by ankle-brachial pressure index (ABI) in a cohort of 71 PXE patients (mean age 48±SD 14 yrs, 45 women) and compared to 30 controls without PAD. Lower limb arterial calcification (LLAC) was determined by non-contrast enhanced helicoidal CT-scan. A calcification score (Ca-score) was computed for the femoral, popliteal and sub-popliteal artery segments of both legs. Forty patients with PXE had an ABI<0.90 and none had an ABI>1.40. LLAC increased with age, significantly more in PXE subjects than controls. A negative association was found between LLAC and ABI (r = −0.363, p = 0.002). The LLAC was independently associated with PXE and age, and ABI was not linked to cardiovascular risk factors.

Conclusions

The presence of AC was associated with PAD and PXE without affecting arterial compressibility. PAD in PXE patients is probably due to proximal obstructive lesions developing independently from cardiovascular risk factors.     

Risk Factors of Cardiovascular Diseases and the Capillary Endothelium in Subjects with Different Levels of Normal Blood Pressure

The capillary circulation in the forearm and crus was studied by occlusion plethysmography at rest and upon stimulation with nitric oxide during reactive hyperemia in 249 virtually healthy subjects with different levels of arterial blood pressure lower than 140/90 mm Hg. Specific features of the microcirculation were found in the forearm and crus depending on the blood pressure level. An increase in the blood pressure higher than 120/80 mm Hg was associated with an increased adverse effect of integral risk factors and heredity on parameters of the capillary circulation, especially in women.     

Postnatal development of arterial pressure: influence of the intrauterine environment

A substantial number of epidemiological studies have shown that small size at birth is associated with an increased risk of developing hypertension and metabolic dysfunction later in life; however these associations have not been found in all studies. In animals, several models have been used to investigate the effects of perturbations to the fetal environment on later arterial pressure, with differing effects on size at birth and arterial pressure. Ovine models include maternal dietary manipulations, antenatal glucocorticoid exposure, and restriction of placental size and function. In our laboratory, we have induced late gestational placental insufficiency and growth restriction in sheep by umbilico-placental embolisation; during the early postnatal period the growth restricted lambs remained small and were hypotensive relative to controls. More recent long-term studies indicate that these growth restricted animals were able to catch up in body weight within the first postnatal year; however, their arterial pressure remained lower than that of controls throughout the first 2 postnatal years (deltaMAP, -4.2 +/- 1.4 mmHg). This relative hypotension may be due to altered vascular or cardiac development resulting from increased vascular resistance or nutrient restriction during fetal life. As late gestational placental insufficiency led to a persistent reduction in arterial pressure from birth to adulthood, our findings do not support the hypothesis that restricted fetal growth per se leads to hypertension after birth. It is likely that the effects of a prenatal compromise on postnatal arterial pressure will vary depending on the nature of the associated developmental perturbations and their gestational timing.     

Biomechanical adaptation of porcine carotid vascular smooth muscle to hypo and hypertension in vitro

Previous research in arterial remodeling in response to changes in blood pressure seldom included both hyper- and hypotension. To compare the effects of low and high pressure on arterial remodeling and vascular smooth muscle tone and performance, we have utilized an in vitro model. Porcine carotid arteries were cultured for 3 days at 30 and 170mmHg and compared to controls cultured at 100mmHg for 1 and 3 days. On the first and last day of culture, pressure-diameter and pressure-wall thickness curves were measured under normal smooth muscle tone using a high-resolution ultrasonic device. Last-day experiments included measurements where vascular smooth muscle was contracted or totally relaxed. From the data wall cross-sectional area, Hudetz elastic modulus and a contraction index related to the diameter reduction under normal smooth muscle tone were calculated. We found that although wall cross-sectional area (indicating wall mass) did not change much, Hudetz elastic modulus was significantly reduced in the 3-day hypotension group. Inspection of the wall contraction index suggests that this is due to a reduction in the vascular smooth muscle tone. Further, the peak of contraction index was found to be shifted to higher pressures in the 3-day 170mmHg group. We conclude that vascular smooth muscle performance adapts to both hypo- and hypertension at short time scales and can alter the biomechanics of the vascular wall in vitro.     

Reduced Blood Pressure of CFTR-F508del Carriers Correlates with Diminished Arterial Reactivity Rather than Circulating Blood Volume in Mice

The F508del mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) is the most common cause of cystic fibrosis (CF). Both CF patients and F508del carriers have decreased blood pressure. While this has been attributed to salt depletion, recent studies have shown F508del expression interferes with smooth muscle cell calcium mobilization. We tested the hypothesis that carriers of the F508del mutation have lower adult blood pressures and reduced aortic contractility without a reduction in circulating blood volume. By radiotelemetry, F508del heterozygous mice had significantly lower arterial pressures than wild-type C57BL/6 controls, with the greatest effect seen at the time of dark-to-light cycle transition (mean difference of 10 mmHg). To replicate the vascular effects of sympathetic arousal, isoproterenol and epinephrine were co-infused, and F508del mice again had significantly reduced arterial pressures. Aortas isolated from F508del heterozygous mice had significantly decreased constriction to noradrenaline (0.9±0.2 versus 2.9±0.7 mN). Inhibition of wild-type CFTR or the inositol triphosphate receptor replicated the phenotype of F508del aortas. CFTR carrier status did not alter circulating blood volume. We conclude the CFTR-F508del mutation decreases aortic contractility and lowers arterial pressures. As a cAMP-activated chloride channel that facilitates calcium mobilization, we speculate wild-type CFTR co-activation during adrenergic receptor stimulation buffers the vasodilatory response to catecholamines, and loss of this compensatory vasoconstrictor tone may contribute to the lower arterial pressures seen in heterozygote carriers of a CFTR-F508del mutation.     

Calf blood flow and vascular resistance during reactive hyperaemia in young athletes and trained middle-aged subjects

The effect of training on dilatation capacity in the lower limbs was evaluated by studying the blood flow and vascular resistance in the calf in 10 young athletes aged 19-29 years and 15 trained middle-aged subjects aged 52-58 years during post-ischaemic reactive hyperaemia. The control groups comprised untrained subjects of approximately the same ages, i.e. 16 men aged 18-29 and 37 aged 40-60. The calf blood flow as determined plethysmographically and the blood pressure was measured on the arm by auscultation. Vascular resistance was calculated from the mean blood pressure and from the maximal calf blood flow measured during hyperaemia. A significantly higher maximal blood flow and significantly lower resistance in the calf were found in young athletes than in untrained subjects. In athletes, the flow debt was significantly overpaid. In middle-aged subjects, the effect of training was manifested only in significant overpayment of the flow debt, while vascular resistance and the maximal blood flow were the same as in the controls. It can be concluded from these findings that significant improvement of vasodilatation ability in association with training occurs primarily in young subjects. The findings also correspond to the known ability of young athletes to give a higher maximal performance than veteran athletes.     

Regulation of Vascular Smooth Muscle Tone by Adipose-Derived Contracting Factor

Obesity and arterial hypertension, important risk factors for atherosclerosis and coronary artery disease, are characterized by an increase in vascular tone. While obesity is known to augment vasoconstrictor prostanoid activity in endothelial cells, less is known about factors released from fat tissue surrounding arteries (perivascular adipose). Using lean controls and mice with either monogenic or diet-induced obesity, we set out to determine whether and through which pathways perivascular adipose affects vascular tone. We unexpectedly found that in the aorta of obese mice, perivascular adipose potentiates vascular contractility to serotonin and phenylephrine, indicating activity of a factor generated by perivascular adipose, which we designated “adipose-derived contracting factor” (ADCF). Inhibition of cyclooxygenase (COX) fully prevented ADCF-mediated contractions, whereas COX-1 or COX-2-selective inhibition was only partially effective. By contrast, inhibition of superoxide anions, NO synthase, or endothelin receptors had no effect on ADCF activity. Perivascular adipose as a source of COX-derived ADCF was further confirmed by detecting increased thromboxane A₂ formation from perivascular adipose-replete aortae from obese mice. Taken together, this study identifies perivascular adipose as a novel regulator of arterial vasoconstriction through the release of COX-derived ADCF. Excessive ADCF activity in perivascular fat under obese conditions likely contributes to increased vascular tone by antagonizing vasodilation. ADCF may thus propagate obesity-dependent hypertension and the associated increased risk in coronary artery disease, potentially representing a novel therapeutic target.