RESUMO
In the CNS, astrocytes are sensory and regulatory hubs that play important roles in cerebral homeostatic processes, including matching local cerebral blood flow to neuronal metabolism (neurovascular coupling). These cells possess a highly branched network of processes that project from the soma to neuronal synapses as well as to arterioles and capillaries, where they terminate in "endfeet" that encase the blood vessels. Ca(2+) signaling within the endfoot mediates neurovascular coupling; thus, these functional microdomains control vascular tone and local perfusion in the brain. Transient receptor potential vanilloid 4 (TRPV4) channels--nonselective cation channels with considerable Ca(2+) conductance--have been identified in astrocytes, but their function is largely unknown. We sought to characterize the influence of TRPV4 channels on Ca(2+) dynamics in the astrocytic endfoot microdomain and assess their role in neurovascular coupling. We identified local TRPV4-mediated Ca(2+) oscillations in endfeet and further found that TRPV4 Ca(2+) signals are amplified and propagated by Ca(2+)-induced Ca(2+) release from inositol trisphosphate receptors (IP3Rs). Moreover, TRPV4-mediated Ca(2+) influx contributes to the endfoot Ca(2+) response to neuronal activation, enhancing the accompanying vasodilation. Our results identify a dynamic synergy between TRPV4 channels and IP3Rs in astrocyte endfeet and demonstrate that TRPV4 channels are engaged in and contribute to neurovascular coupling.
Assuntos
Astrócitos/citologia , Cálcio/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Sinalização do Cálcio , Sistema Nervoso Central/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , OscilometriaRESUMO
The execution and maintenance of all brain functions are dependent on a continuous flow of blood to meet the metabolic needs of the tissue. To ensure the delivery of resources required for neural processing and the maintenance of neural homeostasis, the cerebral vasculature is elaborately and extensively regulated by signaling from neurons, glia, interneurons, and perivascular nerves. Hypertension is associated with impaired neurovascular regulation of the cerebral circulation and culminates in neurodegeneration and cognitive dysfunction. Here, we review the physiological processes of neurovascular signaling in the brain and discuss mechanisms of hypertensive neurovascular dysfunction.
Assuntos
Encéfalo/fisiopatologia , Artérias Cerebrais/inervação , Circulação Cerebrovascular , Hipertensão/fisiopatologia , Transdução de Sinais , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Artérias Cerebrais/patologia , Artérias Cerebrais/fisiopatologia , Humanos , Hipertensão/metabolismo , Hipertensão/patologia , Neuroglia/metabolismo , Neurônios/metabolismoRESUMO
This study examined the effects of anti-TGF-ß antibody (1D11) therapy in Dahl S (S) rats fed a 4% NaCl diet. Baseline renal expression of TGF-ß1 and the degree of injury were lower in female than male S rats maintained on a 0.4% NaCl diet. 4% NaCl diet increased mean arterial pressure (MAP), proteinuria, and renal injury to the same extent in both male and female S rats. Chronic treatment with 1D11 had renoprotective effects in both sexes. The ability of 1D11 to oppose the development of proteinuria when given alone or in combination with antihypertensive agents was further studied in 6-wk-old female S rats, since baseline renal injury was less than that seen in male rats. 1D11, diltiazem, and hydrochlorothiazide (HCT) attenuated the development of hypertension, proteinuria, and glomerular injury. 1D11 had no additional effect when given in combination with these antihypertensive agents. We also explored whether 1D11 could reverse renal injury in 9-wk-old male S rats with preexisting renal injury. MAP increased to 197 ± 4 mmHg and proteinuria rose to >300 mg/day after 3 wk on a 4% NaCl diet. Proteinuria was reduced by 30-40% in rats treated with 1D11, HCT, or captopril + 1D11, but the protective effect was lost in rats fed the 4% NaCl diet for 6 wk. Nevertheless, 1D11, HCT, and captopril + 1D11 still reduced renomedullary and cardiac fibrosis. These results indicate that anti-TGF-ß antibody therapy reduces renal and cardiac fibrosis and affords additional renoprotection when given in combination with various antihypertensive agents in Dahl S rats.
Assuntos
Injúria Renal Aguda/prevenção & controle , Anticorpos Anti-Idiotípicos/imunologia , Anticorpos Anti-Idiotípicos/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Hipertensão/prevenção & controle , Proteinúria/prevenção & controle , Fator de Crescimento Transformador beta/imunologia , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Animais , Anticorpos Anti-Idiotípicos/farmacologia , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Captopril/farmacologia , Captopril/uso terapêutico , Diltiazem/farmacologia , Diltiazem/uso terapêutico , Modelos Animais de Doenças , Feminino , Fibrose , Hidroclorotiazida/farmacologia , Hidroclorotiazida/uso terapêutico , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Masculino , Proteinúria/induzido quimicamente , Proteinúria/metabolismo , Ratos , Ratos Endogâmicos Dahl , Caracteres Sexuais , Cloreto de Sódio na Dieta/efeitos adversosRESUMO
Neuronal activity is communicated to the cerebral vasculature so that adequate perfusion of brain tissue is maintained at all levels of neuronal metabolism. An increase in neuronal activity is accompanied by vasodilation and an increase in local cerebral blood flow. This process, known as neurovascular coupling (NVC) or functional hyperemia, is essential for cerebral homeostasis and survival. Neuronal activity is encoded in astrocytic Ca(2+) signals that travel to astrocytic processes (;endfeet') encasing parenchymal arterioles within the brain. Astrocytic Ca(2+) signals cause the release of vasoactive substances to cause relaxation, and in some circumstances contraction, of the smooth muscle cells (SMCs) of parenchymal arterioles to modulate local cerebral blood flow. Activation of potassium channels in the SMCs has been proposed to mediate NVC. Here, the current state of knowledge of NVC and potassium channels in parenchymal arterioles is reviewed.
Assuntos
Astrócitos/fisiologia , Encéfalo/irrigação sanguínea , Canais de Potássio/fisiologia , Animais , Astrócitos/citologia , Encéfalo/fisiologia , Sinalização do Cálcio/fisiologia , Humanos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/fisiologia , Fluxo Sanguíneo Regional/fisiologia , Vasodilatação/fisiologiaRESUMO
Recent studies have indicated that arachidonic acid (AA) is metabolized by the cytochrome P450 4A (CYP4A) enzymes in cerebral arteries to produce 20-hydroxyeicosatetraenoic acid (20-HETE) and that this compound has effects on cerebral vascular tone that mimic those seen following subarachnoid hemorrhage (SAH). In this regard, 20-HETE is a potent constrictor of cerebral arteries that decreases the open state probability of Ca(2+)-activated K(+) channels through activation of protein kinase C (PKC). It increases the sensitivity of the contractile apparatus to Ca(2+) by activating PKC and rho kinase. The formation of 20-HETE is stimulated by angiotensin II (AII), endothelin, adenosine triphosphate (ATP) and serotonin, and inhibited by NO, CO and superoxide radicals. Inhibitors of the formation of 20-HETE block the myogenic response of cerebral arterioles to elevations in transmural pressure in vitro and autoregulation of cerebral blood flow (CBF) in vivo. 20-HETE also plays an important role in modulating the cerebral vascular responses to vasodilators (NO and CO) and vasoconstrictors (AII, endothelin, serotonin). Recent studies have indicated that the levels of 20-HETE in cerebrospinal fluid (CSF) increase in rats, dogs and human patients following SAH and that inhibitors of the synthesis of 20-HETE prevent the acute fall in CBF in rats and reverse delayed vasospasm in both dogs and rats. This review examines the evidence that an elevation in the production of 20-HETE contributes to the initial fall in CBF following SAH and the later development of delayed vasospasm.
Assuntos
Artérias Cerebrais/metabolismo , Artérias Cerebrais/fisiopatologia , Ácidos Hidroxieicosatetraenoicos/metabolismo , Hemorragia Subaracnóidea/complicações , Vasoespasmo Intracraniano/metabolismo , Vasoespasmo Intracraniano/fisiopatologia , Doença Aguda , Animais , Ácido Araquidônico/biossíntese , Circulação Cerebrovascular/fisiologia , Humanos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologia , Fatores de Tempo , Vasoconstrição/fisiologia , Vasodilatadores/farmacologiaAssuntos
Glicemia/metabolismo , Sinalização do Cálcio , Diabetes Mellitus Tipo 2/metabolismo , Angiopatias Diabéticas/metabolismo , Hiperglicemia/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Proteínas de Ancoragem à Quinase A/metabolismo , Animais , Canais de Cálcio Tipo L/metabolismo , Artérias Cerebrais/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/fisiopatologia , Ativação Enzimática , Humanos , Hiperglicemia/complicações , Hiperglicemia/fisiopatologia , Potenciais da Membrana , Músculo Liso Vascular/fisiopatologia , Proteína Quinase C-alfa/metabolismo , Transdução de Sinais , Regulação para CimaRESUMO
Calcium-sensitive potassium (K(Ca)) channels have been shown to modulate the diameter of cerebral pial arteries; however, little is known regarding their roles in controlling cerebral parenchymal arterioles (PAs). We explored the function and cellular distribution of small-conductance (SK(Ca)) and intermediate-conductance (IK(Ca)) K(Ca) channels and large-conductance K(Ca) (BK(Ca)) channels in endothelial cells (ECs) and smooth muscle cells (SMCs) of PAs. Both SK(Ca) and IK(Ca) channels conducted the outward current in isolated PA ECs (current densities, ~20 pA/pF and ~28 pA/pF at +40 mV, respectively), but these currents were not detected in PA SMCs. In contrast, BK(Ca) currents were prominent in PA SMCs (~154 pA/pF), but were undetectable in PA ECs. Pressurized PAs constricted to inhibition of SK(Ca) (~16%) and IK(Ca) (~16%) channels, but were only modestly affected by inhibition of BK(Ca) channels (~5%). Blockade of SK(Ca) and IK(Ca) channels decreased resting cortical cerebral blood flow (CBF) by ~15%. NS309 (6,7-dichloro-1H-indole-2,3-dione3-oxime), a SK(Ca)/IK(Ca) channel opener, hyperpolarized PA SMCs by ~27 mV, maximally dilated pressurized PAs, and increased CBF by ~40%. In conclusion, these data show that SK(Ca) and IK(Ca) channels in ECs profoundly modulate PA tone and CBF, whereas BK(Ca) channels in SMCs only modestly influence PA diameter.
Assuntos
Arteríolas/metabolismo , Encéfalo/irrigação sanguínea , Circulação Cerebrovascular/fisiologia , Endotélio Vascular/metabolismo , Canais de Potássio Cálcio-Ativados/metabolismo , Animais , Encéfalo/metabolismo , Eletrofisiologia , Células Endoteliais/metabolismo , Imunofluorescência , Masculino , Potenciais da Membrana/fisiologia , Microeletrodos , Músculo Liso Vascular/metabolismo , Ratos , Ratos Sprague-Dawley , Vasodilatação/fisiologiaRESUMO
Aging is associated with peripheral vascular dysfunction. In vascular smooth muscle, cytochrome P450 4A (CYP4A) enzymes form the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE acts as an intracellular messenger to modulate vasoconstriction induced by various agonists, including the alpha1-adrenergic agonist phenylephrine (PE) and endothelin-1 (ET-1). Eicosanoids produced by CYP4A contribute to the elevated vascular tone in hypertension, but the effects of advanced age on CYP4A modulation of vasoconstriction are unknown. Mesenteric arteries were isolated from young (3 to 4 months) and aged (17 to 18 months) Sprague-Dawley rats. Vasoconstriction was induced with PE or ET-1 in the absence or presence of the CYP4A inhibitor DDMS and/or the ETA inhibitor BQ123. CYP4A inhibition with DDMS significantly reduced PE sensitivity in aged rats, but it had no effect in young. Furthermore, in aged rats only, ETA inhibition reduced PE sensitivity while combined inhibition of CYP4A and ETA had no additional effect, suggesting that the pathways work in concert in aging. Exogenous ET-1 constriction was not altered by DDMS in young or aged rats. Overall, our data indicate that aging increases the contribution of CYP4A to alpha1-adrenergic vasoconstriction in systemic arteries. Understanding aging-related changes in vascular function is important for development of novel targets for the prevention of cardiovascular disease.
Assuntos
Envelhecimento , Citocromo P-450 CYP4A/metabolismo , Ácidos Hidroxieicosatetraenoicos/metabolismo , Vasoconstrição/efeitos dos fármacos , Agonistas alfa-Adrenérgicos/farmacologia , Amidas/farmacologia , Animais , Endotelina-1/farmacologia , Masculino , Artérias Mesentéricas , Fenilefrina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/efeitos dos fármacos , Receptor de Endotelina A/metabolismo , Sulfonas/farmacologia , Vasoconstrição/fisiologiaRESUMO
Hypertension is a major risk factor for stroke, but the factors that contribute to the increased incidence and severity of ischemic stroke in hypertension remain to be determined. 20-hydroxyeicosatetraenoic acid (20-HETE) has been reported to be a potent constrictor of cerebral arteries, and inhibitors of 20-HETE formation reduce infarct size following cerebral ischemia. The present study examined whether elevated production of 20-HETE in the cerebral vasculature could contribute to the larger infarct size previously reported after transient middle cerebral artery occlusion (MCAO) in hypertensive strains of rat [spontaneously hypertensive rat (SHR) and spontaneously hypertensive stroke-prone rat (SHRSP)]. The synthesis of 20-HETE in the cerebral vasculature of SHRSP measured by liquid chromatography-tandem mass spectrometry was about twice that seen in Wistar-Kyoto (WKY) rats. This was associated with the elevated expression of cytochrome P-450 (CYP)4A protein and CYP4A1 and CYP4A8 mRNA. Infarct volume after transient MCAO was greater in SHRSP (36+/-4% of hemisphere volume) than in SHR (19+/-5%) or WKY rats (5+/-2%). This was associated with a significantly greater reduction in regional cerebral blood flow (rCBF) in SHR and SHRSP than in WKY rats during the ischemic period (78% vs. 62%). In WKY rats, rCBF returned to 75% of control following reperfusion. In contrast, SHR and SHRSP exhibited a large (166+/-18% of baseline) and sustained (1 h) postischemic hyperperfusion. Acute blockade of the synthesis of 20-HETE with N-hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine (HET0016; 1 mg/kg) reduced infarct size by 59% in SHR and 87% in SHRSP. HET0016 had no effect on the fall in rCBF during MCAO but eliminated the hyperemic response. HET0016 also attenuated vascular O2*- formation and restored endothelium-dependent dilation in cerebral arteries of SHRSP. These results indicate the production of 20-HETE is elevated in the cerebral vasculature of SHRSP and contributes to oxidative stress, endothelial dysfunction, and the enhanced sensitivity to ischemic stroke in this hypertensive model.