Cerebral vascular dysfunction in TallyHo mice: a new model of Type II diabetes

Didion, Sean P.; Lynch, Cynthia M.; Faraci, Frank M.

doi:10.1152/ajpheart.00939.2006

Cited by 41 publications

(36 citation statements)

References 58 publications

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“…Published evidence suggests that 5-HT leads to vasocontraction through the activation of PI3K [1,34] and ROCK [9,29,34,44,47,51] pathways. Moreover, we recently found that the exposure of high insulin led to the augmentation of 5-HTinduced contraction in the carotid arteries obtained from rats through activations of these pathways [58].…”

Section: Effect Of Pi3k Rock or Pdk1 Inhibitors On 5-ht-mediated Comentioning

confidence: 99%

Multiple activation mechanisms of serotonin-mediated contraction in the carotid arteries obtained from spontaneously hypertensive rats

Watanabe

Matsumoto

Ando

et al. 2016

Pflugers Arch - Eur J Physiol

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Serotonin (5-hydroxytryptamine, 5-HT) is an important endogenous substance that regulates the vascular tone, and the abnormal signaling of 5-HT has been observed in the arteries under several pathophysiological conditions such as diabetes and hypertension. However, signaling pathways of 5-HT-mediated vasocontraction in hypertension remain unclear. Therefore, we tested the hypothesis that 5-HT-mediated contraction and contributions of various kinases such as mitogen-activated protein kinases (MAPKs), phosphoinositide 3-kinase (PI3K), Rho kinase (ROCK), and 3-phosphoinositide-dependent kinase 1 (PDK1) to the contraction would be altered in the carotid arteries obtained from spontaneously hypertensive rats (SHR) compared to control Wistar Kyoto (WKY) rats. In the carotid arteries from SHR (vs. those from WKY), (1) the 5-HT-mediated contraction was increased, whereas the norepinephrine-mediated contraction was not; (2) 5-HT-mediated contractions were partly inhibited by each kinase (extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAPK, c-Jun N-terminal kinase (JNK), PI3K, ROCK, and PDK1) inhibitor; and (3) 5-HT-stimulated phosphorylation of ERK1/2, p38 MAPK, JNK, myosin phosphatase target subunit 1 (MYPT1), and PDK1 was increased. The expression of ROCK2 but not ROCK1 was increased in the carotid arteries from SHR compared to WKY. The expression of 5-HT2A receptor, a major receptor of 5-HT-mediated contraction in rat carotid artery, was similar in carotid arteries between the two groups. These results suggest that 5-HT-mediated contraction was utilized multiple signaling pathways such as ERK1/2, p38 MAPK, JNK, PI3K, ROCK, and PDK1. Although 5-HT-mediated contraction was increased in the carotid arteries obtained from SHR, further studies are necessary to clarify how each kinase may integrate in the vascular smooth muscles under hypertension.

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Section: Effect Of Pi3k Rock or Pdk1 Inhibitors On 5-ht-mediated Comentioning

confidence: 99%

Multiple activation mechanisms of serotonin-mediated contraction in the carotid arteries obtained from spontaneously hypertensive rats

Watanabe

Matsumoto

Ando

et al. 2016

Pflugers Arch - Eur J Physiol

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“…[1][2][3][4][5][6][7][8][9][10] Many mechanisms have been proposed to account for impaired eNOSand nNOS-dependent responses of cerebral arteries/ arterioles during diabetes, including the production of a cyclooxygenase constrictor substance, 9 activation of protein kinase C 11,12 and an increase in oxidative stress via activation of multiple cellular pathways. 8,[13][14][15][16][17] Activation of nitric oxide synthases (NOS) has the ability to produce nitric oxide and superoxide. 18,19 The production of nitric oxide requires arginine as a substrate and several cofactors [nicotinamide adenine dinucleotide phosphate hydrogen (NADPH), calcium and tetrahydrobiopterin (BH 4 )] for normal activity.…”

Section: Introductionmentioning

confidence: 99%

Tetrahydrobiopterin rescues impaired responses of cerebral resistance arterioles during type 1 diabetes

Mayhan

Arrick

2016

Diabetes and Vascular Disease Research

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Our goal was to test the hypothesis that administration of tetrahydrobiopterin (BH 4 ) would improve impaired endothelial nitric oxide synthase-dependent dilation of cerebral arterioles during type 1 diabetes. In addition, we examined the influence of BH 4 on levels of superoxide in brain tissue. In vivo diameter of cerebral arterioles in nondiabetic and diabetic rats was measured in response to endothelial nitric oxide synthase-dependent agonists (acetylcholine and adenosine 5′-diphosphate) and an endothelial nitric oxide synthase-independent agonist (nitroglycerine) before and during application of BH 4 (1.0 µM). We also measured levels of superoxide from cortex tissue in nondiabetic and diabetic rats under basal states and during BH 4 . Acetylcholine and adenosine 5′-diphosphate dilated cerebral arterioles in nondiabetic rats, but this vasodilation was significantly impaired in diabetic rats. In contrast, nitroglycerine produced similar vasodilation in nondiabetic and diabetic rats. Application of BH 4 did not enhance vasodilation in nondiabetic rats but improved impaired cerebral vasodilation in diabetic rats. Basal superoxide levels were increased in cortex tissue from diabetic rats, and BH 4 reduced these levels to that found in nondiabetic rats. Thus, BH 4 is an important mediator of endothelial nitric oxide synthase-dependent responses of cerebral arterioles in diabetes and may have therapeutic potential for the treatment of cerebral vascular disease.

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“…Two important mechanisms that contribute to the regulation of cerebral blood perfusion are autoregulatory behavior of cerebral vessels and functional hyperemia upon increased neuronal activity (11,16,20). HFD can negatively affect vascular function, as demonstrated by increased myogenic tone and endothelial dysfunction in dietinduced as well as genetic models of obesity (7,8,24,32,33). The effect of a HFD on neurovascular coupling and cerebrovascular reactivity after an ischemic insult especially in the absence of metabolic abnormalities is unknown.…”

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confidence: 99%

Early effects of high-fat diet on neurovascular function and focal ischemic brain injury

Prakash

Chawla

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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-Obesity is a risk factor for stroke, but the early effects of high-fat diet (HFD) on neurovascular function and ischemic stroke outcomes remain unclear. The goal of this study was to test the hypotheses that HFD beginning early in life 1) impairs neurovascular coupling, 2) causes cerebrovascular dysfunction, and 3) worsens short-term outcomes after cerebral ischemia. Functional hyperemia and parenchymal arteriole (PA) reactivity were measured in rats after 8 wk of HFD. The effect of HFD on basilar artery function after middle cerebral artery occlusion (MCAO) and associated O-GlcNAcylation were assessed. Neuronal cell death, infarct size, hemorrhagic transformation (HT) frequency/severity, and neurological deficit were evaluated after global ischemia and transient MCAO. HFD caused a 10% increase in body weight and doubled adiposity without a change in lipid profile, blood glucose, and blood pressure. Functional hyperemia and PA relaxation were decreased with HFD. Basilar arteries from stroked HFD rats were more sensitive to contractile factors, and acetylcholine-mediated relaxation was impaired. Vascular O-GlcNAcylated protein content was increased with HFD. This group also showed greater mortality rate, infarct volume, HT occurrence rate, and HT severity and poor functional outcome compared with the control diet group. These results indicate that HFD negatively affects neurovascular coupling and cerebrovascular function even in the absence of dyslipidemia. These early cerebrovascular changes may be the cause of greater cerebral injury and poor outcomes of stroke in these animals. cerebral ischemia; high-fat diet; hemorrhagic transformation; neurovascular coupling; vascular dysfunction OBESITY IS an independent risk factor for acute ischemic stroke (AIS) (19,36). An alarming recent report showed that the prevalence of AIS dramatically increased in children and young adults, which positively correlated with increases in risk factors including obesity, lipid disorders, and diabetes (13). Clinical studies also suggest that obesity is an independent predictor of unfavorable functional outcome and mortality in AIS patients treated with tissue plasminogen activator (tPA), the only therapeutic option these patients have (39,40). Given that stroke is the leading cause of disability and that the obesity epidemic is on the rise these clinical and social problems are expected to get worse, and therefore early interventions are necessary. While experimental studies in genetic or diet-induced obesity models have shown increased cerebral infarct size and poor outcomes of stroke (7,25,32,33,41), the early impact of a high-fat diet (HFD) before the development of obesity on AIS injury and functional outcomes is not known.It is known that the brain relies heavily on constant blood flow for proper function. Two important mechanisms that contribute to the regulation of cerebral blood perfusion are autoregulatory behavior of cerebral vessels and functional hyperemia upon increased neuronal activity (11,16,20). HFD can negatively af...

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Cerebral vascular dysfunction in TallyHo mice: a new model of Type II diabetes

Cited by 41 publications

References 58 publications

Multiple activation mechanisms of serotonin-mediated contraction in the carotid arteries obtained from spontaneously hypertensive rats

Multiple activation mechanisms of serotonin-mediated contraction in the carotid arteries obtained from spontaneously hypertensive rats

Tetrahydrobiopterin rescues impaired responses of cerebral resistance arterioles during type 1 diabetes

Early effects of high-fat diet on neurovascular function and focal ischemic brain injury

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