Dysfunction Of Blood Vessels Research Articles

Antiarrhythmic action of natural peptide geroprotector

The study of the biological activity of Slavinorm peptide geroprotector prepared from am extract of cattle vessels was conducted in experimental models of hypertension and calcium chloride-induced arrhythmia. The results of the study showed that, in the experimental rat model of arrhythmia induced by the administration of pituitrin, the intragastric and intramuscular administration of Slavinorm in therapeutic doses led to the leveling of hypertension symptoms, which manifests in the normalization of blood pressure and heart weight, as well as the kidneys and bodies of the animals. In the experimental rat model of calcium chloride-induced arrhythmia and the intragastric and intramuscular administration of Slavinorm can prevent the development of arrhythmia induced by the injection of calcium chloride. The results of the study suggest that further study of this product for the treatment of age-related pathologies associated with blood-vessel dysfunction remains highly relevant.

Antihypertensive effect of formononetin through regulating the expressions of eNOS, 5-HT2A/1B receptors and α1-adrenoceptors in spontaneously rat arteries

One of the main pathological changes of hypertension is the dysfunction of blood vessels. We have found in our previous study that formononetin, one kind of phytoestrogens, has an acute antihypertensive effect. Therefore, we hypothesized that formononetin might produce a chronic antihypertensive effect through regulating the expressions of contractile receptors and endothelial nitric oxide synthase (eNOS) in artery. The present study was conducted to verify this effect. Male spontaneously hypertensive rats (SHRs) were divided into two groups, orally administrated formononetin (50mg/kg per day) and Tween 80 vehicle, respectively, for 8 weeks. The blood pressure was measured by tail-cuff method. Isometric tension of arterial rings was recorded by a myograph system. The mRNA and protein expression in arteries was determined with quantitative real-time polymerase chain reaction and immunohistochemistry, respectively. Results showed that the systolic blood pressure of SHRs decreased significantly in formononetin group compared to Tween 80 group. The vasoconstriction induced by phenylephrine or 5-hydroxytryptamine (5-HT) in the mesenteric artery segments in formononetin group was decreased, and the relaxation induced by acetylcholine was increased compared with that in Tween 80 group. In the mesenteric arteries of the formononetin-treated SHRs, the expressions of α1-adrenoceptors and 5-HT2A/1B receptors at both mRNA and protein levels decreased, while the mRNA and protein expressions of eNOS increased. In conclusion, formononetin has a chronic antihypertensive effect in SHRs. The antihypertensive mechanism may be associated with the down-regulation of α1-adrenoceptors and 5-HT2A/1B receptors, and the up-regulation of eNOS expression in arteries.

N1-methylnicotinamide improves endothelial dysfunction in human blood vessels: Direct evidence at a single cell level

N1-methylnicotinamide improves endothelial dysfunction in human blood vessels: Direct evidence at a single cell level

The effects of cadmium on VEGF‐mediated angiogenesis in HUVECs

Cadmium (Cd) is a highly toxic element that causes morphologic alterations and dysfunction in blood vessels. The altered vascular function caused by cadmium has been implicated in a range of chronic diseases, including hypertension. The effects of cadmium are a multisystem phenomenon involving inflammation, hypertrophy, apoptosis, angiogenesis and important processes involved in vascular remodeling systems. Vascular endothelial growth factor (VEGF) plays a major role in cell growth and angiogenesis under pathologic conditions. VEGF secretion is related to anti-apoptosis protein expression and attenuates apoptosis in endothelial cells. This study examined the VEGF-dependent mechanisms of angiogenesis and apoptosis in cadmium-treated endothelial cells (HUVECs). The effects and mechanisms of cadmium in endothelial cells (HUVECs) were examined by exposing the cells to different doses of cadmium chloride (2.5-40 μ m). After the cadmium treatment, the angiogenesis and apoptosis mechanisms related to VEGF in cadmium-treated HUVECs were examined. As a result, the low concentration of cadmium increased the tube formation in HUVECs. In addition, cadmium at concentrations of 5 and 10 μ m increased VEGF secretion and VEGFR2 activity, which suggest that cadmium affects the growth of blood vessels. All three MAPK pathways, namely ERK, JNK and p38, were activated by cadmium in HUVECs. However, high concentrations of cadmium caused cell damage, disrupted tube formation and inhibited VEGF expression and the activities of VEGFR2 and MAPK in HUVECs. Cadmium has dual functions through VEGF-dependent mechanisms in a dose-dependent manner. In this study, the dual effects of cadmium might alter angiogenesis and induce apoptosis through VEGF pathways in HUVECs.

Role of Nitric Oxide in the Development of Vascular Contractile Dysfunction in Circulatory Shock

Various forms of circulatory shock (including septic shock) lead to an impairment o r vascular function, which importantly contributes to the development of multiple organ failure and mortality. The dysfunction of the blood vessels in shock consists or two principal components: vascular smooth muscle dysfunction, and endothelial dysfunction. The vascular smooth muscle dysfunction (a progressive, therapy-resistant loss or responsiveness of the vascular smooth muscle to vasoconstrictor catecholamines, such as noradrenaline) leads to a progressive deterioration of blood pressure in patients with circulatory shock. The endothelial dysfunction (loss of the ability of the vascular endothelium to produce nitric oxide and other local endothelium-derived factors) contributes to the impairment of microvascular blood flow, to the enhanced adhesion and activation of neutrophils and platelets, to coagulation problems, and perfusion/metabolism mismatch in the affected organs. Here we overview the role of nitric oxide (NO) in the pathogenesis of vascular contractile dysfunction in circulatory shock. We describe the results of published studies involving shock models induced by bacterial lipopolysaccharide (LPS), and by cecal ligation and puncture (CLP), a polymicrobial model of sepsis. Among the many contributing factors, we locus on the role of cyclic GMP (cGMP) dependent pathways as well as a number of cGMP independent pathways. We will also outline the role of oxidative/nitrosative stress, peroxynitrite and poly(ADP-ribose) polymerase (PARP) and vascular potassium channels in the sepsis-associated alterations in vascular smooth muscle contractility.

NO Answer to Alzheimer's Disease?

See related article, pages 1498–1502 What is the cause of Alzheimer's disease? What is the treatment? Currently, there is no (clear) answer. But wait, perhaps NO (nitric oxide) is part of the answer. It is known that amyloid-β peptides (Aβ), the major components of amyloid plaque in Alzheimer's disease, produce endothelial dysfunction in aorta and cerebral blood vessels (Figure).1,–,4 In addition, cardiovascular risk factors and cerebrovascular dysfunction are associated with vascular dementia, as one might expect, but also with Alzheimer's disease.5 Thus, the current state of knowledge is that Aβ produces endothelial dysfunction, and endothelial dysfunction is associated with Alzheimer's disease. Figure. Link between endothelial dysfunction and Alzheimer disease. Left, Risk factors for cardiovascular disease (CVD) are associated with endothelial dysfunction and impairment of modulation of cerebral vasomotor tone by NO/sGC (red) .1,–,3 It also is known that Aβ, which are deposited in amyloid plaques in Alzheimer's disease, generate superoxide and impair NO-mediated vasodilatation.4 Right, The present study6 demonstrates that inhibition of NO/sGC by L-NAME, eNOS deficiency, or ODQ increases APP and the enzyme (BACE1) that cleaves the β-site of APP in brain tissue, and increases Aβ in brain. Because impairment of NO/sGC by several interventions released the “brake” on the APP→Aβ pathway by NO, an implication is that cardiovascular disease risk factors, by impairment of NO/sGC, may also release the brake on APP→Aβ and augment Alzheimer's disease and cerebral amyloid angiopathy …

Progressive Loss of Lymphatic Vessels in Skin of Patients with Systemic Sclerosis

Systemic sclerosis (SSc) is a connective tissue disorder characterized by microvascular and fibrotic changes in the skin and internal organs. The role of blood vessel dysfunction in the pathogenesis of SSc has been extensively investigated, but few studies have addressed the involvement of the lymphatic vascular system. Our aim was to evaluate dermal lymphatic vessels in patients with SSc according to different phases of skin involvement. Skin biopsies were obtained from the forearm of 25 SSc patients (10 early/15 late-stage disease) and 13 healthy controls. Skin sections were immunostained for podoplanin (D2-40), which is selectively expressed in lymphatic endothelial cells, and examined by confocal laser scanning microscopy. Lymphatic vessels were counted in the papillary and reticular dermis. Data were analyzed using Student's t test. The number of lymphatic vessels was significantly reduced in the papillary and reticular dermis of SSc patients compared with controls. In early SSc, lymphatic vessel counts were not different from controls in the papillary dermis, and showed a trend toward a reduction in the reticular dermis. In late SSc, a significant reduction in lymphatic vessels compared with controls was found in both the papillary and reticular dermis. The number of lymphatic vessels in the papillary dermis of late SSc was significantly lower than in early SSc. In SSc, lymphatic microangiopathy is linked to the progression of skin involvement. The progressive disappearance of lymphatic vessels may have a critical pathogenetic role in the progression of SSc from an early edematous phase to overt fibrosis.

Abstract 1291: The neurotransmitter dopamine normalizes tumor neo-vessels by modulating G protein coupled receptor signaling in the cells of tumor microenvironment

Abstract Tumor neo-vessels, unlike the normal are disorganized, tortuous and leaky. Such dysfunctional blood vessels within the tumors pose significant obstacle for the proper delivery of anticancer drugs into the tumor tissues and response to radiation. Thus normalization of these tumor neo-vessels by different approaches has shown to improve the therapeutic efficacies of conventional anti-neoplastic drugs and radiation therapy. We here show for the first time that the neurotransmitter dopamine normalizes tumor blood vessels in mice bearing orthotopic human prostate cancer by manipulating the cellular components of the tumor microenvironment through G protein coupled receptor signaling. This result is significant because dopamine or dopamine like drugs can be utilized synergistically with either anti-cancer drugs or radiation for the treatment of cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1291.

Vascular dysfunction in cerebrovascular disease: mechanisms and therapeutic intervention

The endothelium plays a crucial role in the control of vascular homoeostasis through maintaining the synthesis of the vasoprotective molecule NO* (nitric oxide). Endothelial dysfunction of cerebral blood vessels, manifested as diminished NO* bioavailability, is a common feature of several vascular-related diseases, including hypertension, hypercholesterolaemia, stroke, subarachnoid haemorrhage and Alzheimer's disease. Over the past several years an enormous amount of research has been devoted to understanding the mechanisms underlying endothelial dysfunction. As such, it has become apparent that, although the diseases associated with impaired NO* function are diverse, the underlying causes are similar. For example, compelling evidence indicates that oxidative stress might be an important mechanism of diminished NO* signalling in diverse models of cardiovascular 'high-risk' states and cerebrovascular disease. Although there are several sources of vascular ROS (reactive oxygen species), the enzyme NADPH oxidase is emerging as a strong candidate for the excessive ROS production that is thought to lead to vascular oxidative stress. The purpose of the present review is to outline some of the mechanisms thought to contribute to endothelial dysfunction in the cerebral vasculature during disease. More specifically, we will highlight current evidence for the involvement of ROS, inflammation, the RhoA/Rho-kinase pathway and amyloid beta-peptides. In addition, we will discuss currently available therapies for improving endothelial function and highlight future therapeutic strategies.

Sex Differences in Protection Against Angiotensin II–Induced Endothelial Dysfunction by Manganese Superoxide Dismutase in the Cerebral Circulation

Angiotensin II (Ang II) produces oxidative stress and endothelial dysfunction in blood vessels. The vasculature from females may be protected against deleterious effects of Ang II. We tested the hypothesis that manganese superoxide dismutase (MnSOD) protects against Ang II-induced endothelial dysfunction. Experiments were performed in C57Bl/6, wild-type (MnSOD(+/+)), and MnSOD-deficient (MnSOD(+/-)) mice treated systemically with vehicle or Ang II. Basilar arteries were isolated from mice treated for 1 week with a nonpressor dose of Ang II (0.28 mg/kg per day). Ang II treatment produced superoxide-mediated impairment of responses to the endothelium-dependent vasodilator acetylcholine (P<0.05). In male but not female MnSOD(+/+) mice, Ang II modestly inhibited responses to acetylcholine (P<0.05). In contrast, Ang II selectively impaired these responses by up to 70% in male MnSOD(+/-) mice (P<0.05), and this effect was reversed by Tempol (P<0.05). Ang II had no effect on acetylcholine responses in MnSOD(+/-) female mice. Vascular superoxide levels after treatment with an inhibitor of CuZn and extracellular superoxide dismutase were higher in Ang II-treated versus vehicle-treated MnSOD(+/-) mice. Thus, a nonpressor dose of Ang II produces endothelial dysfunction in male mice only, suggesting that the female vasculature is protected from Ang II. In male but not female mice, MnSOD deficiency enhanced endothelial dysfunction, suggesting that MnSOD normally protects the vasculature during disease states in which Ang II contributes to vascular dysfunction.

Endogenous Interleukin-10 Inhibits Angiotensin II–Induced Vascular Dysfunction

Angiotensin II (Ang II) produces inflammation and endothelial dysfunction in blood vessels. We tested the hypothesis that interleukin 10 (IL-10), an antiinflammatory cytokine, protects against Ang II-induced vascular dysfunction. Responses of carotid arteries from wild-type and IL-10-deficient mice (IL-10(-/-)) were examined in vitro after overnight incubation with vehicle or Ang II (1 nmol/L). In arteries from wild-type mice, acetylcholine (an endothelium-dependent agonist) produced relaxation that was not affected by Ang II. In contrast, relaxation to acetylcholine in arteries from IL-10(-/-) mice was reduced by >50% by Ang II (P<0.05) and this effect was prevented by a scavenger of superoxide. Vascular superoxide increased approximately 2-fold (P<0.05) after treatment with Ang II in IL-10(-/-) mice but not in wild-type. After systemic administration of Ang II (1.4 mg/kg per day for 10 days), Ang II produced modest impairment of endothelial function in wild-type mice but marked impairment in IL-10(-/-) mice (P<0.05) that was reversed by a superoxide scavenger. Increases in arterial pressure in response to Ang II were similar in wild-type and IL-10(-/-) mice. These findings provide the first evidence that endogenous IL-10 limits Ang II-mediated oxidative stress and vascular dysfunction both in vitro and in vivo suggesting that at least some of the protective effects of IL-10 may occur within the vessel wall.

ABT-751, a novel tubulin-binding agent, decreases tumor perfusion and disrupts tumor vasculature

ABT-751 is an orally bioavailable tubulin-binding agent that is currently under clinical development for cancer treatment. In preclinical studies, ABT-751 showed antitumor activity against a broad spectrum of tumor lines including those resistant to conventional chemotherapies. In this study, we investigated the antivascular properties of ABT-751 in a rat subcutaneous tumor model using dynamic contrast-enhanced magnetic resonance imaging. A single dose of ABT-751 (30 mg/kg, intravenously) induced a rapid, transient reduction in tumor perfusion. After 1 h, tumor perfusion decreased by 57% before recovering to near pretreatment levels within 6 h. In contrast, ABT-751 produced little change in muscle perfusion at either time point. To further elucidate mechanisms of drug action at the cellular level, we examined the effects of ABT-751 on endothelial cells using an in-vitro assay. ABT-751, at concentrations corresponding to plasma levels achieved in vivo, caused endothelial cell retraction and significant loss of microtubules within 1 h. The severity of these morphological changes was dose-dependent but reversible within 6 h after the discontinuation of the drug. Taken together, these results show that ABT-751 is a tubulin-binding agent with antivascular properties. Microtubule disruption and morphological changes in vascular endothelial cells may be responsible, at least in part, for the dysfunction of tumor blood vessels after ABT-751 treatment.

Interleukin‐10 Protects Against Vascular Dysfunction with Aging

Aging produces vascular inflammation and dysfunction in blood vessels. We tested the hypothesis that interleukin‐10 (IL‐10), a potent anti‐inflammatory cytokine, protects against aging‐induced vascular dysfunction. Responses of carotid arteries from young (7‐8 mo) and old (19‐20 mo) wild‐type and IL‐10 deficient mice (IL‐10‐/‐) were examined in vitro. In arteries from wild‐type mice, acetylcholine (an endothelium‐dependent agonist) produced relaxation that was not altered at this age. In contrast, relaxation to acetylcholine in arteries from IL‐10 deficient mice was markedly impaired with age. For example, relaxation of the carotid artery to 10 μmol/L acetylcholine was 87±3 and 48±2% in old wild‐type versus old IL‐10 deficient mice, respectively (P&lt;0.01). Tempol (1 mM), a scavenger of superoxide, did not affect responses in young or old wild‐type or young IL‐10 deficient mice, but restored vasodilation to acetylcholine to normal in old IL‐10 deficient mice. Relaxation of the carotid artery to nitroprusside was not altered in any group. These findings provide the first evidence that age‐related and superoxide‐mediated endothelial dysfunction occurred much earlier and to a greater extent with IL‐10 deficiency. Our findings suggest a novel role for IL‐10 in oxidative stress and age‐related vascular dysfunction.

Neutrophils contribute to intracerebral haemorrhages after treatment with recombinant tissue plasminogen activator following cerebral ischaemia

Polymorphonuclear neutrophils (PMNs) contribute to the vascular damage caused by transient cerebral ischaemia. Here we have evaluated the role of PMNs in intracerebral haemorrhage (ICH) induced in a model of thrombolysis with recombinant tissue plasminogen activator (t-PA) during the acute phase of cerebral ischaemia. The middle cerebral artery (MCA) of male spontaneously hypertensive rats was occluded for 1 h followed by reperfusion and, 5 h later, infusion of thrombolytic products (generated in vitro by t-PA on autologous clots). Effects of pretreatment (before the MCA occlusion) with vinblastine (4 days before; 0.5 mg.kg(-1)), monoclonal anti-neutrophil antibody (mAbRP3; 12 h, 0.3 mg.kg(-1)) or saline on ICH, neutrophil infiltration, MCA vascular reactivity and brain infarct volume were assessed, 24 h after the beginning of reperfusion. Depletion of circulating neutrophils significantly reduced t-PA-induced ICH (vinblastine, 4.6 +/- 1.0; mAbRP3, 5.2 +/- 1.0 vs. saline, 10.8 +/- 2.7 haemorrhages; P < 0.05). This depletion was associated with a decrease in cerebral infiltration by neutrophils and a decrease of endothelium-dependent, vascular dysfunction in isolated MCA, induced by the ischaemia/reperfusion and t-PA treatment. Brain infarct volume was significantly decreased after vinblastine treatment (159 +/- 13 mm(3) vs. 243 +/- 16 mm(3) with saline; P < 0.01) but not after depletion with mAbRP3 (221 +/- 22 mm(3)). Our results showed that pharmacological depletion of PMNs prevented t-PA-induced ICH, in parallel with a decrease in cerebral infiltration by PMNs and a decreased endothelial dysfunction in cerebral blood vessels.

Ergot Alkaloid Induced Blood Vessel Dysfunction Contributes to Fescue Toxicosis

Ergot Alkaloid Induced Blood Vessel Dysfunction Contributes to Fescue Toxicosis

Oxidative Stress in the Pathogenesis/Treatment of Diabetes and its Complications

In diabetes oxidative stress plays a key role in the pathogenesis of vascular complications, and an early step of such damage is considered the development of an endothelial dysfunction. Hyperglycemia directly promotes an endothelial dysfunction inducing process of overproduction of superoxide and consequently peroxynitrite that damages DNA and activates the nuclear enzyme poly(ADP-ribose) polymerase. This process, depleting NAD+, slowing glycolisis, ATP formation and electron transport, results in acute endothelial dysfunction in diabetic blood vessels and contributes to the development of diabetic complications. These new findings may explain why classical antioxidants, like vitamin E, that work scavenging already formed toxic oxidation products, have failed to show beneficial effects on diabetic complications, and suggest new and attractive “causal” antioxidant therapy. New, low molecular mass compounds that act as SOD or catalase mimetics or L-propionyl-carnitine and lipoic acid, that work as intracellular superoxide scavengers, improving mitochondrial function and reducing DNA damage, may be good candidates for such strategy, and preliminary studies support this hypothesis. This “causal” therapy would also be associated with other promising tools such as LY 333531, PJ34 and FP15, which block protein kinase β isoform, poly(ADP-ribose) polymerase and peroxynitrite, respectively. It is now evident that, statins, ACE inhibitors, AT-1 blockers, calcium channel blockers and thiazolinediones have a strong intracellular antioxidant activity, and it has been suggested that many of their beneficial ancillary effects are due to this property. This preventive activity against oxidative stress generation can justify a large utilization and association of this compounds for preventing complications in diabetic patients where antioxidant defences have been shown to be defective.

Intermittent hypoxia changes HIF-1α phosphorylation pattern in endothelial cells: Unravelling of a new PKA-dependent regulation of HIF-1α

Vascularized tumors are exposed to intermittent hypoxia, that is, hypoxia followed by periods of reoxygenation. Abnormal structure and dysfunction of tumor blood vessels are responsible for these conditions. These repeated short periods of hypoxia concern tumor cells as well as endothelial cells. However, the effects of intermittent hypoxia are poorly understood. The aim of this study was to investigate the effects of intermittent hypoxia on endothelial cells and particularly on HIF-1α, a central actor in adaptive response to hypoxia. For that, endothelial cells were exposed to four repeated cycles of 1-h hypoxia followed by 30 min of reoxygenation. We showed that repeated cycles of hypoxia/reoxygenation induced a modification in HIF-lα phosphorylation pattern: a progressive increase in HIF-1α phosphorylated form was observed during the hypoxic periods. Activation of p42/p44, Akt and PKA was observed in parallel. PKA was shown to be involved in the phosphorylation of HIF-lα under intermittent hypoxia, while p42/p44 and Akt were not. As HIF-1 activity is often associated with enhanced cell survival, a better knowledge of the effects of intermittent hypoxia on endothelial cells and the highlight of particular mechanisms induced by intermittent hypoxia are essential to understand the behavior of endothelial cells during neo-angiogenesis.

Ocular Neovascularization: Basic Mechanisms and Therapeutic Advances

The vast majority of diseases that cause catastrophic loss of vision do so as a result of ocular neovascularization. During normal retinal vascular development, vascular endothelial cells proliferate and migrate through the extracellular matrix in response to a variety of cytokines, leading to the formation of new blood vessels in a highly ordered fashion. During abnormal neovascularization of the iris, retina, or choroid, angiogenesis is unregulated and usually results in the formation of dysfunctional blood vessels. When these newly formed vessels leak fluid, hemorrhage, or are associated with fibrous proliferation, retinal edema, retinal/vitreous hemorrhage, or traction retinal detachments may occur resulting in potentially catastrophic loss of vision. In this review, we will briefly discuss the scope of the clinical problem and the general underlying principles of angiogenesis. We will focus on recent laboratory advances that have led to the development of therapeutics useful in the treatment of neovascular eye diseases. We will describe compounds currently in pre-clinical development stages as well as the results of clinical trials involving the use of these drugs as treatments for ocular neovascularization.

CuZn Superoxide Dismutase Deficiency

Impairment of endothelium-dependent responses is an early landmark of endothelial dysfunction in blood vessels with aging and/or cardiovascular diseases.1 A critical manifestation of endothelial dysfunction is the reduced bioavailability of NO, a key vascular protective molecule and an independent predictor of cardiovascular events.2 Hence, stimuli decreasing vascular NO bioavailability manifest impaired endothelium-dependent relaxation. Aging is associated with marked changes in the cardiovascular system, especially at the level of the vascular wall.3 Both structural and functional changes can take place at the level of the endothelium, vascular smooth muscle cell (VSMC), and the extracellular matrix of blood vessels. Endothelial thickening and altered endothelium-dependent responses have been reported in aged animals. Clinical studies have also shown that endothelium-dependent relaxation of both conduit and resistance vessels declines progressively with age. In contrast, endothelium-independent relaxation to sodium nitroprusside is unaffected by aging, suggesting that the impaired relaxation with age is primarily because of the dysfunctional endothelium, rather than VSMC contraction.3 Although the mechanisms underlying the aging-induced endothelial dysfunction are complex and incompletely understood, oxidative stress is a key contributor.4 Exposure of endothelial cells to increased levels of reactive oxygen species (ROS) during the aging process makes them a prime target for oxidative stress. As the first and initiating oxygen free radical in the ROS chain, superoxide (O2−) consumption of NO is one of the most important mechanisms of endothelial dysfunction.5 Vascular cells possess multifaceted protective mechanisms against the toxic effects of ROS.4–6 Among them, the 3 superoxide dismutase (SOD) isoforms, the cytosolic copper zinc SOD (CuZnSOD, SOD-1), mitochondrial manganese SOD (MnSOD, SOD-2), and extracellular SOD (EC-SOD, SOD-3), have evolved as the key enzymatic defense system for converting O2− to hydrogen peroxide (H …

Impairment of Dilator Responses of Cerebral Arterioles During Diabetes Mellitus

During diabetes, expression of inducible nitric oxide synthase (iNOS) plays an important role in the development of endothelial dysfunction in extracranial blood vessels. Progression of vascular dysfunction after the onset of diabetes differs among vascular beds. In this study, the effects of hyperglycemia/diabetes on vasomotor function were examined in cerebral arterioles at 2 different times in control and iNOS-deficient mice and compared with the effects on carotid arteries. Streptozotocin (150 mg/kg IP) was given to induce diabetes. The diameter of cerebral arterioles was measured through a cranial window in diabetic and nondiabetic mice in vivo. Vasomotor function of the carotid artery was examined in vitro. In diabetic mice, responses of the cerebral arterioles to acetylcholine (1 mumol/L) were normal after 3 weeks of diabetes but were significantly impaired after 5 to 6 weeks of diabetes (4+/-1% [mean+/-SEM] increase in diameter) compared with control mice (14+/-1; P=0.0002). Responses to sodium nitroprusside were similar in diabetic and nondiabetic mice at both time points. In contrast, the vasomotor function of the carotid artery was not affected after 5 to 6 weeks of diabetes. In diabetic iNOS-deficient mice, cerebral arteriolar vasomotor function was not impaired, even after 4 months of diabetes. During diabetes, endothelial dysfunction of cerebral arterioles requires expression of iNOS and develops earlier than in carotid arteries.