RESUMO
Palmitoylation is the most common post-translational lipid modification in the brain; however, the role of palmitoylation and palmitoylating enzymes in the nervous system remains elusive. One of these enzymes, Zdhhc5, has previously been shown to regulate synapse plasticity. Here, we report that Zdhhc5 is also essential for the formation of excitatory, but not inhibitory, synapses both in vitro and in vivo. We demonstrate in vitro that this is dependent on the enzymatic activity of Zdhhc5, its localization at the plasma membrane and its C-terminal domain, which has been shown to be truncated in a patient with schizophrenia. Loss of Zdhhc5 in mice results in a decrease in the density of excitatory hippocampal synapses accompanied by alterations in membrane capacitance and synaptic currents, consistent with an overall decrease in spine number and silent synapses. These findings reveal an important role for Zdhhc5 in the formation and/or maintenance of excitatory synapses.
Assuntos
Aciltransferases , Sinapses , Aciltransferases/genética , Aciltransferases/metabolismo , Animais , Membrana Celular/metabolismo , Hipocampo/metabolismo , Humanos , Lipoilação , Camundongos , Sinapses/metabolismoRESUMO
OBJECTIVE: Parenchymal arterioles (PAs) regulate perfusion of the cerebral microcirculation, and impaired PA endothelium-dependent dilation occurs in dementia models mimicking chronic cerebral hypoperfusion (CCH). Epoxyeicosatrienoic acids (EETs) are vasodilators; their actions are potentiated by soluble epoxide hydrolase (sEH) inhibition. We hypothesized that chronic sEH inhibition with trifluoromethoxyphenyl-3 (1-propionylpiperidin-4-yl) urea (TPPU) would prevent cognitive dysfunction and improve PA dilation in a hypertensive CCH model. METHODS: Bilateral carotid artery stenosis (BCAS) was used to induce CCH in twenty-week-old male stroke-prone spontaneously hypertensive rats (SHSRP) that were treated with vehicle or TPPU for 8 weeks. Cognitive function was assessed by novel object recognition. PA dilation and structure were assessed by pressure myography, and mRNA expression in brain tissue was assessed by qRT-PCR. RESULTS: TPPU did not enhance resting cerebral perfusion, but prevented CCH-induced memory deficits. TPPU improved PA endothelium-dependent dilation but reduced the sensitivity of PAs to a nitric oxide donor. TPPU treatment had no effect on PA structure or biomechanical properties. TPPU treatment increased brain mRNA expression of brain derived neurotrophic factor, doublecortin, tumor necrosis factor-alpha, sEH, and superoxide dismutase 3, CONCLUSIONS: These data suggest that sEH inhibitors may be viable treatments for cognitive impairments associated with hypertension and CCH.
Assuntos
Isquemia Encefálica , Circulação Cerebrovascular/efeitos dos fármacos , Cognição/efeitos dos fármacos , Epóxido Hidrolases/antagonistas & inibidores , Hipertensão , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/enzimologia , Dilatação , Proteína Duplacortina , Inibidores Enzimáticos/química , Epóxido Hidrolases/metabolismo , Hipertensão/tratamento farmacológico , Hipertensão/enzimologia , Masculino , Ratos , Ratos Endogâmicos SHRRESUMO
Hypertension is a leading risk factor for vascular cognitive impairment and is strongly associated with carotid artery stenosis. In normotensive rats, chronic cerebral hypoperfusion induced by bilateral common carotid artery stenosis (BCAS) leads to cognitive impairment that is associated with impaired endothelium-dependent dilation in parenchymal arterioles (PAs). The aim of this study was to assess the effects of BCAS on PA function and structure in stroke-prone spontaneously hypertensive rats, a model of human essential hypertension. Understanding the effects of hypoperfusion on PAs in a hypertensive model could lead to the identification of therapeutic targets for cognitive decline in a model that reflects the at-risk population. We hypothesized that BCAS would impair endothelium-dependent dilation in PAs and induce artery remodeling compared with sham rats. PAs from BCAS rats had endothelial dysfunction, as assessed using pressure myography. Inhibition of nitric oxide and prostaglandin production had no effect on PA dilation in sham or BCAS rats. Surprisingly, inhibition of epoxyeicosatrienoic acid production increased dilation in PAs from BCAS rats but not from sham rats. Similar results were observed in the presence of inhibitors for all three dilatory pathways, suggesting that epoxygenase inhibition may have restored a nitric oxide/prostaglandin-independent dilatory pathway in PAs from BCAS rats. PAs from BCAS rats underwent remodeling with a reduced wall thickness. These data suggest that marked endothelial dysfunction in PAs from stroke-prone spontaneously hypertensive rats with BCAS may be associated with the development of vascular cognitive impairment. NEW & NOTEWORTHY The present study assessed the structure and function of parenchymal arterioles in a model of chronic cerebral hypoperfusion and hypertension, both of which are risk factors for cognitive impairment. We observed that impaired dilation and artery remodeling in parenchymal arterioles and abolished cerebrovascular reserve capacity may mediate cognitive deficits.
Assuntos
Arteríolas/fisiopatologia , Encéfalo/irrigação sanguínea , Artéria Carótida Primitiva/fisiopatologia , Estenose das Carótidas/fisiopatologia , Circulação Cerebrovascular , Hipertensão/fisiopatologia , Tecido Parenquimatoso/irrigação sanguínea , Vasodilatação , Animais , Arteríolas/metabolismo , Comportamento Animal , Artéria Carótida Primitiva/metabolismo , Estenose das Carótidas/complicações , Estenose das Carótidas/metabolismo , Transtornos Cerebrovasculares/etiologia , Transtornos Cerebrovasculares/metabolismo , Transtornos Cerebrovasculares/fisiopatologia , Transtornos Cerebrovasculares/psicologia , Cognição , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/psicologia , Modelos Animais de Doenças , Hipertensão/complicações , Hipertensão/metabolismo , Masculino , Memória , Ratos Endogâmicos SHR , Transdução de Sinais , Remodelação VascularRESUMO
Chronic cerebral hypoperfusion is a risk factor for cognitive impairment. Reduced blood flow through the common carotid arteries induced by bilateral carotid artery stenosis (BCAS) is a physiologically relevant model of chronic cerebral hypoperfusion. We hypothesized that BCAS in 20-wk-old Wistar-Kyoto (WKY) rats would impair cognitive function and lead to reduced endothelium-dependent dilation and outward remodeling in the parenchymal arterioles (PAs). After 8 wk of BCAS, both short-term memory and spatial discrimination abilities were impaired. In vivo assessment of cerebrovascular reserve capacity showed a severe impairment after BCAS. PA endothelial function and structure were assessed by pressure myography. BCAS impaired endothelial function in PAs, as evidenced by reduced dilation to carbachol. Addition of nitric oxide synthase and cyclooxygenase inhibitors did not change carbachol-mediated dilation in either group. Inhibiting CYP epoxygenase, the enzyme that produces epoxyeicosatrienoic acid (EETs), a key determinant of endothelium-derived hyperpolarizing factor (EDHF)-mediated dilation, abolished dilation in PAs from Sham rats, but had no effect in PAs from BCAS rats. Expression of TRPV4 channels, a target for EETs, was decreased and maximal dilation to a TRPV4 agonist was attenuated after BCAS. Together these data suggest that EET-mediated dilation is impaired in PAs after BCAS. Thus impaired endothelium-dependent dilation in the PAs may be one of the contributing factors to the cognitive impairment observed after BCAS.
Assuntos
Arteríolas/fisiopatologia , Encéfalo/irrigação sanguínea , Artéria Carótida Primitiva/fisiopatologia , Estenose das Carótidas/fisiopatologia , Transtornos Cerebrovasculares/fisiopatologia , Endotélio Vascular/fisiopatologia , Vasodilatação , Animais , Arteríolas/metabolismo , Comportamento Animal , Artéria Carótida Primitiva/cirurgia , Estenose das Carótidas/complicações , Circulação Cerebrovascular , Transtornos Cerebrovasculares/etiologia , Transtornos Cerebrovasculares/metabolismo , Transtornos Cerebrovasculares/psicologia , Cognição , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/psicologia , Modelos Animais de Doenças , Eicosanoides/metabolismo , Endotélio Vascular/metabolismo , Ligadura , Memória de Curto Prazo , Ratos Endogâmicos WKY , Fluxo Sanguíneo Regional , Comportamento Espacial , Canais de Cátion TRPV/metabolismo , Fatores de TempoRESUMO
OBJECTIVE: Chronic hypertension induces detrimental changes in the structure and function of surface cerebral arteries. Very little is known about PAs, which perfuse distinct neuronal populations in the cortex and may play a role in cerebrovascular disorders. We investigated the effect of DOCA-salt induced hypertension on endothelial function and artery structure in PAs and MCAs. METHODS: Uninephrectomized male Sprague-Dawley rats were implanted with a subcutaneous pellet containing DOCA (150 mg/kg b.w.) and drank salt water (1% NaCl and 0.2% KCl) for 4 weeks. Sham rats were uninephrectomized and drank tap water. Vasoreactivity and passive structure in the MCAs and the PAs were assessed by pressure myography. RESULTS: Both MCAs and PAs from DOCA-salt rats exhibited impaired endothelium-dependent dilation (P<.05). In the PAs, addition of NO and COX inhibitors enhanced dilation in DOCA-salt rats (P<.05), suggesting that dysfunctional NO and COX-dependent signaling could contribute to impaired endothelium-mediated dilation. MCAs from DOCA-salt rats exhibited inward remodeling (P<.05). CONCLUSIONS: Hypertension-induced MCA remodeling coupled with impaired endothelium-dependent dilation in both the MCAs and PAs may exacerbate the risk of cerebrovascular accidents and the associated morbidity and mortality.
Assuntos
Artérias Cerebrais/fisiopatologia , Hipertensão/fisiopatologia , Animais , Arteríolas/fisiopatologia , Inibidores de Ciclo-Oxigenase/farmacologia , Acetato de Desoxicorticosterona/farmacologia , Endotélio Vascular , Hipertensão/induzido quimicamente , Masculino , Artéria Cerebral Média/fisiopatologia , Miografia/métodos , Óxido Nítrico/farmacologia , Tecido Parenquimatoso/irrigação sanguínea , Ratos , Ratos Sprague-Dawley , Vasodilatação/efeitos dos fármacosRESUMO
Maintenance of brain function depends on a constant blood supply. Deficits in cerebral blood flow are linked to cognitive decline, and they have detrimental effects on the outcome of ischemia. Hypertension causes alterations in cerebral artery structure and function that can impair blood flow, particularly during an ischemic insult or during periods of low arterial pressure. This review will focus on the historical discoveries, novel developments, and knowledge gaps in 1) hypertensive cerebral artery remodeling, 2) vascular function with emphasis on myogenic reactivity and endothelium-dependent dilation, and 3) blood-brain barrier function. Hypertensive artery remodeling results in reduction in the lumen diameter and an increase in the wall-to-lumen ratio in most cerebral arteries; this is linked to reduced blood flow postischemia and increased ischemic damage. Many factors that are increased in hypertension stimulate remodeling; these include the renin-angiotensin-aldosterone system and reactive oxygen species levels. Endothelial function, vital for endothelium-mediated dilation and regulation of myogenic reactivity, is impaired in hypertension. This is a consequence of alterations in vasodilator mechanisms involving nitric oxide, epoxyeicosatrienoic acids, and ion channels, including calcium-activated potassium channels and transient receptor potential vanilloid channel 4. Hypertension causes blood-brain barrier breakdown by mechanisms involving inflammation, oxidative stress, and vasoactive circulating molecules. This exposes neurons to cytotoxic molecules, leading to neuronal loss, cognitive decline, and impaired recovery from ischemia. As the population ages and the incidence of hypertension, stroke, and dementia increases, it is imperative that we gain a better understanding of the control of cerebral artery function in health and disease.
Assuntos
Circulação Cerebrovascular , Hipertensão/fisiopatologia , Animais , Artérias Cerebrais/patologia , Artérias Cerebrais/fisiopatologia , Humanos , Sistema Renina-Angiotensina , VasoconstriçãoRESUMO
Dynamic protein S-palmitoylation is critical for neuronal function, development, and synaptic plasticity. Synaptic activity-dependent changes in palmitoylation have been reported for a small number of proteins. Here, we characterized the palmitoylome in the hippocampi of male mice before and after context-dependent fear conditioning. Of the 121 differentially palmitoylated proteins identified, just over half were synaptic proteins, whereas others were associated with metabolic functions, cytoskeletal organization, and signal transduction. The synapse-associated proteins generally exhibited increased palmitoylation after fear conditioning. In contrast, most of the proteins that exhibited decreased palmitoylation were associated with metabolic processes. Similar results were seen in cultured rat hippocampal neurons in response to chemically induced long-term potentiation. Furthermore, we found that the palmitoylation of one of the synaptic proteins, plasticity-related gene-1 (PRG-1), also known as lipid phosphate phosphatase-related protein type 4 (LPPR4), was important for synaptic activity-induced insertion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) into the postsynaptic membrane. The findings identify proteins whose dynamic palmitoylation may regulate their role in synaptic plasticity, learning, and memory.
Assuntos
Hipocampo , Animais , Masculino , Camundongos , RatosAssuntos
Pesquisa Biomédica , Mentores , Farmacologia , Pesquisadores , Toxicologia , Escolha da Profissão , Comunicação , Humanos , Relações Interpessoais , EnsinoRESUMO
We aimed to create a clinically relevant pre-clinical model of transient hypertension, and then evaluate the pathophysiological cerebrovascular processes resulting from this novel stimulus, which has recently been epidemiologically linked to cerebrovascular disease. We first developed a clinically relevant model of transient hypertension, secondary to induced autonomic dysreflexia after spinal cord injury and demonstrated that in both patients and rats, this stimulus leads to drastic acute cerebral hyperperfusion. For this, iatrogenic urodynamic filling/penile vibrostimulation was completed while measuring beat-by-beat blood pressure and cerebral blood flow (CBF) in patients. We then developed a rodent model mimicking the clinical reality by performing colorectal distention (to induce autonomic dysreflexia) using pre-clinical beat-by-beat blood pressure and CBF assessments. We then performed colorectal distension in rats for four weeks (6x/day) to evaluate the long-term cerebrovascular consequences of transient hypertension. Outcome measures included middle cerebral artery endothelial function, remodeling, profibrosis and perivascular innervation; measured via pressure myography, immunohistochemistry, molecular biology, and magnetic resonance imaging. Our model demonstrates that chronic repetitive cerebral hyperperfusion secondary to transient hypertension because of autonomic dysreflexia: (1) impairs cerebrovascular endothelial function; (2) leads to profibrotic cerebrovascular stiffening characterized by reduced distensibility and increased collagen deposition; and (3) reduces perivascular sympathetic cerebrovascular innervation. These changes did not occur concurrent to hallmark cerebrovascular changes from chronic steady-state hypertension, such as hypertrophic inward remodeling, or reduced CBF. Chronic exposure to repetitive transient hypertension after spinal cord injury leads to diverse cerebrovascular impairment that appears to be unique pathophysiology compared with steady-state hypertension in non-spinal cord injured models.
Assuntos
Disreflexia Autonômica/fisiopatologia , Encéfalo/fisiopatologia , Circulação Cerebrovascular/fisiologia , Hipertensão/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia , Adulto , Animais , Encéfalo/patologia , Endotélio Vascular/fisiopatologia , Fibrose/patologia , Humanos , Masculino , Ratos , Traumatismos da Medula Espinal/patologiaRESUMO
The incidence of obesity in the population is increasing at an alarming rate, with this comes an increased risk of insulin resistance (IR). Obesity and IR increase an individual's risk of having a stroke and they have been linked to several forms of dementia. Stroke and dementia are associated with, or exacerbated by, reduced cerebral blood flow, which has recently been described in obese patients. In this review we will discuss the effects of obesity on cerebral artery function and structure. Regarding their function, we will focus on the endothelium and nitric oxide (NO) dependent dilation. NO dependent dilation is impaired in cerebral arteries from obese rats, and the majority of evidence suggests this is a result of increased oxidative stress. We will also describe the limited studies showing that inward cerebral artery remodeling occurs in models of obesity, and that the remodeling is associated with an increase in the damage caused by cerebral ischemia. We will also discuss some of the more paradoxical findings associated with stroke and obesity, including the evidence that obesity is a positive factor for stroke survival. Finally we will discuss the evidence that links these changes in vascular structure and function to cognitive decline and dementia.