Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 49
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33430047

RESUMO

We aimed to determine whether an experimental model of hyperthyroidism could alter the function of sympathetic and nitrergic components of mesenteric innervation. For this purpose, male Wistar rats were divided into (1) control rats (CT) and (2) rats infused with L-Thyroxine (HT). Body weight gain and adipose tissue accumulation were lower in HT rats, while systolic blood pressure and citrate synthase activity in the soleus muscle were increased by HT. In segments from the superior mesenteric artery, the application of an electrical field stimulation (EFS) induced a vasoconstrictor response, which was lower in arteries from HT animals. The alpha-adrenoceptor antagonist phentolamine diminished EFS-induced vasoconstriction to a lower extent in HT arteries, while the purinergic receptor antagonist suramin reduced contractile response to EFS only in segments from CT. In line with this, noradrenaline release, tyrosine hydroxylase expression and activation and dopamine ß hydroxylase expression were diminished in HT. The unspecific nitric oxide synthase (NOS) inhibitor L-NAME increased EFS-induced vasoconstriction more markedly in segments from HT rats. NO release was enhanced in HT, probably due to an enhancement in neuronal NOS activity, in which a hyperactivation of both PKC and PI3K-AKT signaling pathways might play a relevant role. In conclusion, perivascular mesenteric innervation might contribute to reduce the vascular resistance observed in hyperthyroidism.


Assuntos
Peso Corporal/efeitos dos fármacos , Hipertireoidismo/genética , Óxido Nítrico Sintase/genética , Óxido Nítrico/genética , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/crescimento & desenvolvimento , Animais , Peso Corporal/genética , Modelos Animais de Doenças , Estimulação Elétrica , Humanos , Hipertireoidismo/metabolismo , Hipertireoidismo/patologia , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/crescimento & desenvolvimento , Veias Mesentéricas/efeitos dos fármacos , Veias Mesentéricas/crescimento & desenvolvimento , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Ratos , Ratos Wistar , Tiroxina/farmacologia , Vasoconstrição/genética
2.
J Vasc Surg ; 74(1): 79-89.e2, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33340698

RESUMO

OBJECTIVE: To evaluate the outcomes of various surgical approaches in the treatment of renovascular hypertension and midaortic syndrome (MAS) in children. METHODS: We performed a retrospective medical record review of patients who had undergone surgery for renovascular hypertension from 2010 to 2018 at our center under the care of a multidisciplinary team. The operative interventions included mesenteric artery growth improves circulation (MAGIC), tissue expander-stimulated lengthening of arteries (TESLA), aortic bypass using polytetrafluorethylene, renal artery reimplantation, and autotransplantation. The MAGIC procedure uses the meandering mesenteric artery as a free conduit for aortic bypass. The TESLA procedure is based on lengthening the normal distal aorta and iliac arteries by gradual filling of a retroaortic tissue expander for several weeks, followed by resection of the stenotic aorta and subsequent primary reconstruction. RESULTS: A total of 39 patients were identified, 10 with isolated renal artery stenosis, 26 with MAS, and 3 with systemic inflammatory vasculitis. The median age at presentation and surgery was 6.4 years (range, 0-16.3 years) and 9.3 years (range, 0-9.2 years), respectively. The MAS-associated syndromes included neurofibromatosis type 1 (15.4%) and Williams syndrome (5.1%), although most cases were idiopathic. At surgery, 33.3% had had stage 1 hypertension (HTN), 53.8% stage 2 HTN, and 12.8% normal blood pressure with a median of three antihypertensive medications. Follow-up of 37 patients at a median of 2.5 years demonstrated normal blood pressure in 86.1%, stage 1 HTN in 8.3%, and stage 2 HTN in 5.6%, with a median of one antihypertensive medication for the entire cohort. CONCLUSIONS: The patterns of vascular involvement leading to renovascular hypertension in children are variable and complex, requiring thoughtful multidisciplinary planning and surgical decision-making. The MAGIC and TESLA procedures provide feasible approaches for aortic bypass and reconstruction using autologous tissues and will result in normalization of blood pressure in 85% of children 2.5 years after surgery.


Assuntos
Aorta/cirurgia , Doenças da Aorta/cirurgia , Arteriopatias Oclusivas/cirurgia , Hipertensão Renovascular/cirurgia , Obstrução da Artéria Renal/cirurgia , Procedimentos Cirúrgicos Vasculares , Adolescente , Fatores Etários , Aorta/diagnóstico por imagem , Aorta/fisiopatologia , Doenças da Aorta/complicações , Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/fisiopatologia , Arteriopatias Oclusivas/complicações , Arteriopatias Oclusivas/diagnóstico por imagem , Arteriopatias Oclusivas/fisiopatologia , Pressão Sanguínea , Prótese Vascular , Implante de Prótese Vascular/instrumentação , Criança , Pré-Escolar , Feminino , Humanos , Hipertensão Renovascular/diagnóstico , Hipertensão Renovascular/etiologia , Hipertensão Renovascular/fisiopatologia , Artéria Ilíaca/fisiopatologia , Artéria Ilíaca/cirurgia , Lactente , Masculino , Artérias Mesentéricas/crescimento & desenvolvimento , Artérias Mesentéricas/fisiopatologia , Artérias Mesentéricas/transplante , Artéria Renal/fisiopatologia , Artéria Renal/cirurgia , Obstrução da Artéria Renal/diagnóstico por imagem , Obstrução da Artéria Renal/etiologia , Obstrução da Artéria Renal/fisiopatologia , Reimplante , Estudos Retrospectivos , Síndrome , Fatores de Tempo , Expansão de Tecido/instrumentação , Dispositivos para Expansão de Tecidos , Transplante Autólogo , Resultado do Tratamento , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Procedimentos Cirúrgicos Vasculares/instrumentação
3.
Physiol Rep ; 6(17): e13863, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30198176

RESUMO

The myogenic response (MR) and myogenic tone (MT) in resistance vessels is crucial for maintaining peripheral vascular resistance and blood flow autoregulation. Development of MT involves G protein-coupled receptors, and may be affected by aging. AIMS: (1) to estimate the mesenteric blood flow in myogenically active small mesenteric arteries; (2) to investigate the signaling from Gαq/11 and/or Gα12 activation to MT development; (3) to investigate the role of Rho-kinase 2 and aging on MT in mesenteric resistance arteries. METHODS: we used pressure myography, quantitative real-time PCR, and immunolocalization to study small (<200 µm) mesenteric arteries (SMA) from young, mature adult, and middle aged mice. RESULTS: Poiseuille flow calculations indicated autoregulation of blood flow at 60-120 mm Hg arterial pressure. Gαq/11 and Gα12 were abundantly expressed at the mRNA and protein levels in SMA. The Gαq/11 inhibitor YM-254890 suppressed MT development, and the Phosholipase C inhibitors U73122 and ET-18-OCH3 robustly inhibited it. We found an age-dependent increase in ROCK2 mRNA expression, and in basal MT. The specific ROCK2 inhibitor KD025 robustly inhibited MT in SMAs in all mice with an age-dependent variation in KD025 sensitivity. The inhibitory effect of KD025 was not prevented by the L-type Ca2+ channel activator BayK 8644. KD025 reversibly inhibited MT and endothelin-1 vasoconstriction in small pial arteries from Göttingen minipigs. CONCLUSIONS: MT development in SMAs occurs through a Gαq/11 /PLC/Ca2+ -dependent pathway, and is maintained via ROCK2-mediated Ca2+ sensitization. Increased MT at mature adulthood can be explained by increased ROCK2 expression/activity.


Assuntos
Envelhecimento/fisiologia , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Artérias Mesentéricas/metabolismo , Músculo Liso Vascular/fisiologia , Transdução de Sinais , Quinases Associadas a rho/metabolismo , Envelhecimento/metabolismo , Animais , Canais de Cálcio Tipo L/metabolismo , Subunidades alfa de Proteínas de Ligação ao GTP/antagonistas & inibidores , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Masculino , Artérias Mesentéricas/crescimento & desenvolvimento , Artérias Mesentéricas/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Tono Muscular , Músculo Liso Vascular/crescimento & desenvolvimento , Músculo Liso Vascular/metabolismo , Suínos , Porco Miniatura , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/genética
4.
Pflugers Arch ; 470(2): 355-365, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29082441

RESUMO

Impairment of endothelial function with aging is accompanied by reduced nitric oxide (NO) production. T-type Cav3.1 channels augment nitric oxide and co-localize with eNOS. Therefore, the hypothesis was that T-type channels contribute to the endothelial dysfunction of aging. Endothelial function was determined in mesenteric arteries (perfusion) and aortae (isometric contraction) of young and old wild-type (WT), Cav3.1, and Cav3.2 knockout mice. NO production was measured by fluorescence imaging in mesenteric arteries. With age, endothelium-dependent subsequent dilatation (following depolarization with KCl) of mesenteric arteries was diminished in the arteries of WT mice, unchanged in Cav3.2-/- preparations but increased in those of Cav3.1-/- mice. NO synthase inhibition abolished the subsequent dilatation in mesenteric arteries and acetylcholine-induced relaxations in aortae. NO levels were significantly reduced in mesenteric arteries of old compared to young WT mice. In Cav3.1-/- and Cav3.2-/- preparations, NO levels increased significantly with age. Relaxations to acetylcholine were significantly smaller in the aortae of old compared to young WT mice, while such responses were comparable in preparations of young and old Cav3.1-/- and Cav3.2-/- mice. The expression of Cav3.1 was significantly reduced in aortae from aged compared to young WT mice. The level of phosphorylated eNOS was significantly increased in aortae from aged Cav3.1-/- mice. In conclusion, T-type calcium channel-deficient mice develop less age-dependent endothelial dysfunction. Changes in NO levels are involved in this phenomenon in WT and Cav3.1-/- mice. These findings suggest that T-type channels play an important role in age-induced endothelial dysfunction.


Assuntos
Envelhecimento/metabolismo , Canais de Cálcio Tipo T/metabolismo , Endotélio Vascular/fisiologia , Envelhecimento/fisiologia , Animais , Aorta/crescimento & desenvolvimento , Aorta/metabolismo , Aorta/fisiologia , Canais de Cálcio Tipo T/genética , Endotélio Vascular/metabolismo , Feminino , Deleção de Genes , Masculino , Artérias Mesentéricas/crescimento & desenvolvimento , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Vasoconstrição , Vasodilatação
6.
Physiol Rep ; 5(23)2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29212858

RESUMO

High-fat sucrose (HFS) diet in aged individuals causes severe weight gain (obesity) with much higher risk of cardiovascular diseases such as hypertension or atherosclerosis. Endothelial dysfunction is a major contributor for these vascular disorders. We hypothesize that prolonged ingestion of HFS diet by aged mice would accentuate endothelial dysfunction in the small resistance arteries. Male C57BL/6J mice at 12 weeks of age were divided into four groups and fed either normal chow (NC) or high-fat sucrose diet (HFS). Young group received NC for 4 months, and high-fat diet (HFD) for 3 months and 1 month HFS + 10% Sucrose (HFS diet). Aged mice received NC for 12 months. Aged HFS group received HFD for 4 months + 1 month HFD + 10% sucrose + 8 months HFD. Total body weight, plasma blood glucose levels, and glucose tolerance were determined in all groups. Isolated mesenteric arteries were assessed for arterial remodeling, myogenic tone, and vasomotor responses using pressure and wire myography. Both young and aged HFS mice showed impaired glucose tolerance (Y-NC, 137 ± 8.5 vs. Y-NC HFS, 228 ± 11.71; A-NC, 148 ± 6.42 vs. A-HFS, 225 ± 10.99), as well as hypercholesterolemia (Y-NC 99.50 ± 6.35 vs. Y-HFS 220.40 ± 16.34 mg/dL; A-NC 108.6 ± vs. A-HFS 279 ± 21.64) and significant weight gain (Y-NC 32.13 ± 0.8 g vs. Y-HFS 47.87 ± 2.18 g; A-NC 33.72 vs. A-HFS 56.28 ± 3.47 g) compared to both groups of mice on NC. The mesenteric artery from mice with prolonged HFS diet resulted in outward hypertrophic remodeling, increased stiffness, reduced myogenic tone, impaired vasodilation, increased contractility and blunted nitric oxide (NO) and EDH-mediated relaxations. Ebselen, a peroxinitrite scavenger rescued the endothelium derived relaxing factor (EDHF)-mediated relaxations. Our findings suggest that prolonged diet-induced obesity of aged mice can worsen small resistance artery endothelial dysfunction due to decrease in NO and EDHF-mediated relaxation, but, EDHF-mediated relaxation is a major contributor to overall endothelial dysfunction.


Assuntos
Fatores Biológicos/metabolismo , Dieta Hiperlipídica/efeitos adversos , Sacarose Alimentar/efeitos adversos , Artérias Mesentéricas/fisiopatologia , Doenças Vasculares/etiologia , Vasodilatação , Animais , Sacarose Alimentar/administração & dosagem , Endotélio Vascular/crescimento & desenvolvimento , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Masculino , Artérias Mesentéricas/crescimento & desenvolvimento , Artérias Mesentéricas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Tono Muscular , Óxido Nítrico/metabolismo , Doenças Vasculares/metabolismo , Doenças Vasculares/fisiopatologia , Rigidez Vascular , Vasoconstrição
7.
Peptides ; 84: 36-43, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27545826

RESUMO

UNLABELLED: The influence of intracellular renin on the inward calcium current in isolated smooth muscle cells from SHR mesenteric arteries was investigated. Measurements of calcium current were performed using the whole cell configuration of pCLAMP. The results indicated that: 1) renin (100nM) dialyzed into smooth muscle cells, increased the inward calcium current; 2) verapamil (10-9M) administered to the bath inhibited the effect of renin on the inward calcium current; 3) concurrently with the increase of calcium current a depolarization of 6.8+/-2.1mV (n=16)(P<0.05) was found in cells dialyzed with renin; 4) intracellular dialysis of renin (100nM) into smooth muscle cells isolated from mesenteric arteries of normal Wystar Kyoto rats showed no significant change on calcium current; 5) aliskiren (10-9M) dialyzed into the cell together with renin (100nM) abolished the effect of the enzyme on the calcium current in SHR; 6) Ang II (100nM) dialyzed into the smooth muscle cell from mesenteric artery of SHR in absence of renin, decreased the calcium current-an effect greatly reduced by valsartan (10-9M) added to the cytosol; 7) administration of renin (100nM) plus angiotensinogen (100nM) into the cytosol of muscles cells from SHR rats reduced the inward calcium current; 8) extracellular administration of Ang II (100nM) increased the inward calcium current in mesenteric arteries of SHR. CONCLUSIONS: intracellular renin in vascular resistance vessels from SHR due to internalization or expression, contributes to the regulation of vascular tone and control of peripheral resistance-an effect independently of Ang II. Implications for hypertension and vascular remodeling are discussed.


Assuntos
Hipertensão/metabolismo , Artérias Mesentéricas/metabolismo , Miócitos de Músculo Liso/metabolismo , Renina/metabolismo , Amidas/administração & dosagem , Angiotensina II/administração & dosagem , Animais , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Modelos Animais de Doenças , Fumaratos/administração & dosagem , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/patologia , Artérias Mesentéricas/crescimento & desenvolvimento , Miócitos de Músculo Liso/efeitos dos fármacos , Ratos , Renina/genética , Remodelação Vascular/efeitos dos fármacos , Verapamil/administração & dosagem
8.
J Physiol ; 594(8): 2323-38, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26010764

RESUMO

KEY POINTS: The dilatory role for sensory innervation of mesenteric arteries (MAs) is impaired in Old (∼24 months) versus Young (∼4 months) mice. We investigated the nature of this impairment in isolated pressurized MAs. With perivascular sensory nerve stimulation, dilatation and inhibition of sympathetic vasoconstriction observed in Young MAs were lost in Old MAs along with impaired dilatation to calcitonin gene-related peptide (CGRP). Inhibiting NO and prostaglandin synthesis increased CGRP EC50 in Young and Old MAs. Endothelial denudation attenuated dilatation to CGRP in Old MAs yet enhanced dilatation to CGRP in Young MAs while abolishing all dilatations to ACh. In Old MAs, sensory nerve density was reduced and RAMP1 (CGRP receptor component) associated with nuclear regions of endothelial cells in a manner not seen in Young MAs or in smooth muscle cells of either age. With advanced age, loss of dilatory signalling mediated through perivascular sensory nerves may compromise perfusion of visceral organs. ABSTRACT: Vascular dysfunction and sympathetic nerve activity increase with advancing age. In the gut, blood flow is governed by perivascular sensory and sympathetic nerves but little is known of how their functional role is affected by advanced age. We tested the hypothesis that functional sensory innervation of mesenteric arteries (MAs) is impaired for Old (24 months) versus Young (4 months) C57BL/6 male mice. In cannulated pressurized MAs preconstricted 50% with noradrenaline and treated with guanethidine (to inhibit sympathetic neurotransmission), perivascular nerve stimulation (PNS) evoked dilatation in Young but not Old MAs while dilatations to ACh were not different between age groups. In Young MAs, capsaicin (to inhibit sensory neurotransmission) blocked dilatation and increased constriction during PNS. With no difference in efficacy, the EC50 of CGRP as a vasodilator was ∼6-fold greater in Old versus Young MAs. Inhibiting nitric oxide (l-NAME) and prostaglandin (indomethacin) synthesis increased CGRP EC50 in both age groups. Endothelial denudation reduced the efficacy of dilatation to CGRP by ∼30% in Old MAs yet increased this efficacy ∼15% in Young MAs while all dilatations to ACh were abolished. Immunolabelling revealed reduced density of sensory (CGRP) but not sympathetic (tyrosine hydroxylase) innervation for Old versus Young MAs. Whereas the distribution of CGRP receptor proteins was similar in SMCs, RAMP1 associated with nuclear regions of endothelial cells of Old but not Young MAs. With advanced age, the loss of sensory nerve function and diminished effectiveness of CGRP as a vasodilator is multifaceted and may adversely affect splanchnic perfusion.


Assuntos
Envelhecimento/fisiologia , Artérias Mesentéricas/inervação , Células Receptoras Sensoriais/fisiologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Endotélio Vascular/crescimento & desenvolvimento , Endotélio Vascular/metabolismo , Artérias Mesentéricas/crescimento & desenvolvimento , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Prostaglandinas/metabolismo , Proteína 1 Modificadora da Atividade de Receptores/metabolismo , Vasodilatação
9.
Am J Physiol Heart Circ Physiol ; 309(9): H1468-78, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26371173

RESUMO

We examined the effect of stress in the first 2 wk of life induced by brief periods of daily maternal separation on developmental programming of rat small resistance mesenteric arteries (MAs). In MAs of littermate controls, mRNAs encoding mediators of vasoconstriction, including the α1a-adrenergic receptor, smooth muscle myosin heavy chain, and CPI-17, the inhibitory subunit of myosin phosphatase, increased from after birth through sexual [postnatal day (PND) 35] and full maturity, up to ∼80-fold, as measured by quantitative PCR. This was commensurate with two- to fivefold increases in maximum force production to KCl depolarization, calcium, and the α-adrenergic agonist phenylephrine, and increasing systolic blood pressure. Rats exposed to maternal separation stress as neonates had markedly accelerated trajectories of maturation of arterial contractile gene expression and function measured at PND14 or PND21 (weaning), 1 wk after the end of the stress protocol. This was suppressed by the α-adrenergic receptor blocker terazosin (0.5 mg·kg ip(-1)·day(-1)), indicating dependence on stress activation of sympathetic signaling. Due to the continued maturation of MAs in control rats, by sexual maturity (PND35) and into adulthood, no differences were observed in arterial function or response to a second stressor in rats stressed as neonates. Thus early life stress misprograms resistance artery smooth muscle, increasing vasoconstrictor function and blood pressure. This effect wanes in later stages, suggesting plasticity during arterial maturation. Further studies are indicated to determine whether stress in different periods of arterial maturation may cause misprogramming persisting through maturity and the potential salutary effect of α-adrenergic blockade in suppression of this response.


Assuntos
Pressão Sanguínea/genética , Regulação da Expressão Gênica no Desenvolvimento , Privação Materna , Artérias Mesentéricas/metabolismo , Músculo Liso Vascular/metabolismo , RNA Mensageiro/metabolismo , Estresse Psicológico/genética , Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Animais , Animais Recém-Nascidos , Pressão Sanguínea/efeitos dos fármacos , Artérias Mesentéricas/crescimento & desenvolvimento , Proteínas Musculares/genética , Músculo Liso Vascular/crescimento & desenvolvimento , Cadeias Pesadas de Miosina/genética , Quinase de Cadeia Leve de Miosina/genética , Fenilefrina/farmacologia , Fosfoproteínas/genética , Prazosina/análogos & derivados , Prazosina/farmacologia , Proteína Fosfatase 1/genética , Ratos , Receptores Adrenérgicos alfa 1/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estresse Psicológico/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/genética , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/genética
10.
J Clin Invest ; 124(7): 3230-40, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24937433

RESUMO

Autonomic sympathetic nerves innervate peripheral resistance arteries, thereby regulating vascular tone and controlling blood supply to organs. Despite the fundamental importance of blood flow control, how sympathetic arterial innervation develops remains largely unknown. Here, we identified the axon guidance cue netrin-1 as an essential factor required for development of arterial innervation in mice. Netrin-1 was produced by arterial smooth muscle cells (SMCs) at the onset of innervation, and arterial innervation required the interaction of netrin-1 with its receptor, deleted in colorectal cancer (DCC), on sympathetic growth cones. Function-blocking approaches, including cell type-specific deletion of the genes encoding Ntn1 in SMCs and Dcc in sympathetic neurons, led to severe and selective reduction of sympathetic innervation and to defective vasoconstriction in resistance arteries. These findings indicate that netrin-1 and DCC are critical for the control of arterial innervation and blood flow regulation in peripheral organs.


Assuntos
Artérias Mesentéricas/inervação , Fatores de Crescimento Neural/fisiologia , Sistema Nervoso Simpático/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Animais , Animais Recém-Nascidos , Receptor DCC , Feminino , Cones de Crescimento/fisiologia , Masculino , Artérias Mesentéricas/crescimento & desenvolvimento , Artérias Mesentéricas/fisiologia , Camundongos , Camundongos Knockout , Camundongos Mutantes , Camundongos Transgênicos , Modelos Neurológicos , Miócitos de Músculo Liso/fisiologia , Fatores de Crescimento Neural/deficiência , Fatores de Crescimento Neural/genética , Netrina-1 , Gravidez , Receptores de Superfície Celular/fisiologia , Sistema Nervoso Simpático/crescimento & desenvolvimento , Proteínas Supressoras de Tumor/deficiência , Proteínas Supressoras de Tumor/genética , Vasoconstrição/fisiologia
11.
Am J Physiol Heart Circ Physiol ; 307(4): H563-73, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-24929853

RESUMO

There is evidence for developmental origins of vascular dysfunction yet little understanding of maturation of vascular smooth muscle (VSM) of regional circulations. We measured maturational changes in expression of myosin phosphatase (MP) and the broader VSM gene program in relation to mesenteric small resistance artery (SRA) function. We then tested the role of the sympathetic nervous system (SNS) in programming of SRAs and used genetically engineered mice to define the role of MP isoforms in the functional maturation of the mesenteric circulation. Maturation of rat mesenteric SRAs as measured by qPCR and immunoblotting begins after the second postnatal week and is not complete until maturity. It is characterized by induction of markers of VSM differentiation (smMHC, γ-, α-actin), CPI-17, an inhibitory subunit of MP and a key target of α-adrenergic vasoconstriction, α1-adrenergic, purinergic X1, and neuropeptide Y1 receptors of sympathetic signaling. Functional correlates include maturational increases in α-adrenergic-mediated force and calcium sensitization of force production (MP inhibition) measured in first-order mesenteric arteries ex vivo. The MP regulatory subunit Mypt1 E24+/LZ- isoform is specifically upregulated in SRAs during maturation. Conditional deletion of mouse Mypt1 E24 demonstrates that splicing of E24 causes the maturational reduction in sensitivity to cGMP-mediated vasorelaxation (MP activation). Neonatal chemical sympathectomy (6-hydroxydopamine) suppresses maturation of SRAs with minimal effect on a conduit artery. Mechanical denervation of the mature rat renal artery causes a reversion to the immature gene program. We conclude that the SNS captures control of the mesenteric circulation by programming maturation of the SRA smooth muscle.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Artérias Mesentéricas/metabolismo , Artéria Renal/metabolismo , Sistema Nervoso Simpático/fisiologia , Actinas/genética , Actinas/metabolismo , Animais , Diferenciação Celular , GMP Cíclico/metabolismo , Masculino , Artérias Mesentéricas/crescimento & desenvolvimento , Artérias Mesentéricas/inervação , Camundongos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiologia , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Quinase de Cadeia Leve de Miosina/genética , Quinase de Cadeia Leve de Miosina/metabolismo , Fosfatase de Miosina-de-Cadeia-Leve/genética , Fosfatase de Miosina-de-Cadeia-Leve/metabolismo , Ratos , Ratos Sprague-Dawley , Artéria Renal/crescimento & desenvolvimento , Artéria Renal/inervação , Sistema Nervoso Simpático/crescimento & desenvolvimento , Vasoconstrição , Vasodilatadores/farmacologia
12.
Am J Physiol Heart Circ Physiol ; 307(4): H504-14, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-24929854

RESUMO

In resistance arteries, a chronic increase in blood flow induces hypertrophic outward remodeling. This flow-mediated remodeling (FMR) is absent in male rats aged 10 mo and more. As FMR depends on estrogens in 3-mo-old female rats, we hypothesized that it might be preserved in 12-mo-old female rats. Blood flow was increased in vivo in mesenteric resistance arteries after ligation of the side arteries in 3- and 12-mo-old male and female rats. After 2 wk, high-flow (HF) and normal-flow (NF) arteries were isolated for in vitro analysis. Arterial diameter and cross-sectional area increased in HF arteries compared with NF arteries in 3-mo-old male and female rats. In 12-mo-old rats, diameter increased only in female rats. Endothelial nitric oxide synthase expression and endothelium-mediated relaxation were higher in HF arteries than in NF arteries in all groups. ERK1/2 phosphorylation, NADPH oxidase subunit expression levels, and arterial contractility to KCl and to phenylephrine were greater in HF vessels than in NF vessels in 12-mo-old male rats only. Ovariectomy in 12-mo-old female rats induced a similar pattern with an increased contractility without diameter increase in HF arteries. Treatment of 12-mo-old male rats and ovariectomized female rats with hydralazine, the antioxidant tempol, or the angiotensin II type 1 receptor blocker candesartan restored HF remodeling and normalized arterial contractility in HF vessels. Thus, we found that FMR of resistance arteries remains efficient in 12-mo-old female rats compared with age-matched male rats. A balance between estrogens and vascular contractility might preserve FMR in mature female rats.


Assuntos
Estrogênios/metabolismo , Artérias Mesentéricas/fisiologia , Remodelação Vascular , Resistência Vascular , Fatores Etários , Animais , Benzimidazóis/farmacologia , Compostos de Bifenilo , Óxidos N-Cíclicos/farmacologia , Estrogênios/farmacologia , Feminino , Hidralazina/farmacologia , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/crescimento & desenvolvimento , Artérias Mesentéricas/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NADPH Oxidases/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Ratos Wistar , Marcadores de Spin , Tetrazóis/farmacologia , Vasoconstrição , Vasoconstritores/farmacologia , Vasodilatação , Vasodilatadores/farmacologia
13.
Artigo em Inglês | MEDLINE | ID: mdl-23963637

RESUMO

This study was designed to clarify development and the neural regulation of longitudinal smooth muscle in the chicken posterior mesenteric artery to generate new hypotheses for the roles of arterial longitudinal muscles. The existence of longitudinal muscles was examined with hematoxylin-eosin staining. A well-developed longitudinal muscle layer exists in the posterior mesenteric artery of adult female chickens but not adult male chickens. The muscle layer is poorly developed in chickens aged < 15 weeks, even in female chickens. Mechanical responses of muscles were recorded and perivascular nerves were stimulated by electrical field stimulation (EFS). EFS induced monophasic contractions in longitudinal muscle of the posterior mesenteric artery segment, and those responses were inhibited by pretreatment with tetrodotoxin. Blockers for cholinoceptors and adrenoceptors did not affect EFS-evoked contractions but an antagonist for P2X purinoceptors blocked them. The present study demonstrated that the longitudinal muscle in the posterior mesenteric artery of the domestic fowl develops between the 5th and 15th week of life, suggesting that its development is involved in oviposition. The longitudinal muscle might have a role in resisting extensional stress from the oviduct containing eggs. Moreover, the arterial longitudinal muscle is regulated by purinergic neurons via P2X purinoceptors.


Assuntos
Desenvolvimento Muscular , Receptores Purinérgicos P2X/metabolismo , Transdução de Sinais , Vasoconstrição , Antagonistas Adrenérgicos/farmacologia , Fatores Etários , Animais , Galinhas , Estimulação Elétrica , Feminino , Regulação da Expressão Gênica , Artérias Mesentéricas/crescimento & desenvolvimento , Artérias Mesentéricas/metabolismo , Antagonistas Muscarínicos/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/crescimento & desenvolvimento , Músculo Liso Vascular/inervação , Antagonistas do Receptor Purinérgico P2X/farmacologia , RNA Mensageiro/metabolismo , Receptores Purinérgicos P2X/efeitos dos fármacos , Receptores Purinérgicos P2X/genética
14.
J Comp Physiol B ; 181(8): 1063-73, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21626136

RESUMO

At birth, the intestine becomes the sole site for nutrient absorption requiring a dramatic increase in blood flow. The vascular changes accompanying this transition have been partly characterized in mammals. We investigated, using wire myography, the developmental changes in chick mesenteric artery (MA) reactivity. Rings of the MA from 15-day (E15) and 19-day (E19) chicken embryos (total incubation 21 days) as well as non-fed 0-3-h-old (NH3h) and first-fed 1-day-old (NH1d) newly hatched chicks contracted in response to KCl, norepinephrine (NE), U46619, and endothelin (ET)-1 and relaxed in response to acetylcholine (ACh), sodium nitroprusside (SNP), and forskolin indicating the presence of electro- and pharmaco-mechanical coupling as well as cGMP- and cAMP-mediated relaxation. In ovo development and transition to ex ovo life was accompanied by alterations in the response of the MAs, but a different developmental trajectory was observed for each reactivity pathway tested. Thus, the contractile efficacy of KCl underwent a linear increase (E15 < E19 < NH3h < NH1d). The efficacy of NE and U46619 increased in ovo, but not ex ovo (E15 < E19 = NH3h = NH1d) and the efficacy of ET-1 peaked at E19 (E15 < E19 > NH3h = NH1d). The relaxations elicited by ACh (endothelium-dependent), SNP, and forskolin did not undergo significant developmental changes. In conclusion, the ability of chick MAs to constrict in response to pharmacological stimuli increases during the embryonic period, but no dramatic changes are induced by hatching or the first feeding. Maturation of vasodilator mechanisms precedes that of vasoconstrictor mechanisms. Alterations of the delicate balance between vasoconstrictors and vasodilators may play an important role in perinatal intestinal diseases.


Assuntos
Galinhas/fisiologia , Desenvolvimento Embrionário/fisiologia , Artérias Mesentéricas/crescimento & desenvolvimento , Vasoconstrição/fisiologia , Vasodilatação/fisiologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Acetilcolina/farmacologia , Animais , Animais Recém-Nascidos , Peso Corporal/fisiologia , Embrião de Galinha , Colforsina/farmacologia , Endotelina-1/farmacologia , Inibidores Enzimáticos/farmacologia , Artérias Mesentéricas/anatomia & histologia , NG-Nitroarginina Metil Éster/farmacologia , Nitroprussiato/farmacologia , Norepinefrina/farmacologia , Oxidiazóis/farmacologia , Cloreto de Potássio/farmacologia , Quinoxalinas/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
15.
J Vasc Res ; 47(2): 108-14, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-19729957

RESUMO

Aging is a major risk factor for the development of cardiovascular diseases, including arterial occlusive disease. Oxidant stress increases with age, and may be a significant factor contributing to vascular dysfunction and disease. We have shown that aging and hypertension impair collateral growth, the natural compensatory response to arterial occlusive disease, and that antioxidants restore collateral growth in young hypertensive rats. The aim of this study was to test the hypothesis that oxidant stress mediates collateral growth impairment in nondiseased, aged rats. Ileal arteries were induced to become collaterals via ligation of adjacent arteries. Growth was assessed at 7 days by repeated in vivo measurements and comparison to same-animal control arteries. Collateral diameter enlargement did not occur in aged rats, but luminal expansion was stimulated by pretreatment with tempol. Co-administration of L-NAME with tempol prevented tempol-mediated collateral development. Expression of p22(phox) mRNA was increased in aged versus young rat arteries, suggesting NAD(P)H oxidase as a source of reactive oxygen species. Treatment with apocynin increased collateral growth capacity, whether administered prior to, or 7 days following, arterial ligation. The results suggest that antioxidant treatment may be useful in promoting collateral growth to compensate for age-related arterial occlusive disease.


Assuntos
Acetofenonas/farmacologia , Envelhecimento , Antioxidantes/farmacologia , Circulação Colateral/efeitos dos fármacos , Óxidos N-Cíclicos/farmacologia , Íleo/irrigação sanguínea , Oclusão Vascular Mesentérica/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Fatores Etários , Animais , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Ligadura , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/crescimento & desenvolvimento , Artérias Mesentéricas/cirurgia , Oclusão Vascular Mesentérica/metabolismo , Oclusão Vascular Mesentérica/fisiopatologia , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos WKY , Ratos Wistar , Marcadores de Spin
16.
J Vasc Res ; 44(5): 403-9, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17551259

RESUMO

BACKGROUND/METHODS: We applied a novel method for studying endothelial cells (EC) by using autoradiography of cells labeled by 3H-thymidine: photo emulsion was administered into the vascular bed. In the flat transparent organ, this method allows to compare the mitotic activity of endothelium (MAE) depending on vessel diameter and animal age. RESULTS: The number of the labeled ECs in animals was found to be almost equal in all vessels at the same age. The amount of labeled vessels and the density of the labeled nuclei increase towards near-capillary vessels of a diameter < or =10 microm. With age, MAE decreases in all categories of vessels. However, in 12-day-old animals, MAE temporarily increases. It was noted that high MAE in the bed of these rats precedes or coincides with the period of accelerated weight gain of the digestive system supplied by an increase in organ blood flow. CONCLUSIONS: By using the endothelial autoradiography method that we developed, we obtained the following evidence: (1) the number of ECs in the synthetic phase of the mitotic cycle in mesenterial vessels is approximately identical in animals of the same age, and (2) this number decreases with age, except during the period of accelerated organ growth, when MAE increases.


Assuntos
Autorradiografia/métodos , Células Endoteliais/citologia , Endotélio Vascular/citologia , Artérias Mesentéricas/citologia , Veias Mesentéricas/citologia , Fatores Etários , Animais , Animais Lactentes , Aorta Torácica , Cateteres de Demora , Divisão Celular , Replicação do DNA , Emulsões/administração & dosagem , Injeções Intra-Arteriais , Intestinos/irrigação sanguínea , Intestinos/crescimento & desenvolvimento , Fígado/irrigação sanguínea , Fígado/crescimento & desenvolvimento , Artérias Mesentéricas/crescimento & desenvolvimento , Veias Mesentéricas/crescimento & desenvolvimento , Mesentério/irrigação sanguínea , Mesentério/crescimento & desenvolvimento , Especificidade de Órgãos , Ratos , Ratos Wistar , Fluxo Sanguíneo Regional , Timidina/metabolismo , Trítio/análise
17.
Am J Physiol Heart Circ Physiol ; 292(5): H2523-31, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17277018

RESUMO

Recent clinical and animal studies have shown that collateral artery growth is impaired in the presence of vascular risk factors, including hypertension. Available evidence suggests that angiotensin-converting enzyme inhibitors (ACEI) promote collateral growth in both hypertensive humans and animals; however, the specific mechanisms are not established. This study evaluated the hypothesis that collateral growth impairment in hypertension is mediated by excess superoxide produced by NAD(P)H oxidase in response to stimulation of the ANG II type 1 receptor. After ileal artery ligation, mesenteric collateral growth did not occur in untreated, young, spontaneously hypertensive rats. Significant luminal expansion occurred in collaterals of spontaneously hypertensive rats treated with the superoxide dismutase mimetic tempol, the NAD(P)H oxidase inhibitor apocynin, and the ACEI captopril, but not ANG II type 1 (losartan) or type 2 (PD-123319) receptor blockers. The ACEI enalapril produced equivalent reduction of arterial pressure as captopril but did not promote luminal expansion. This suggests the effects of captopril on collateral growth might result from its antioxidant properties. RT-PCR demonstrated that ANG II type 1 receptor and angiotensinogen expression was reduced in collaterals of untreated rats. This local suppression of the renin angiotensin system provides a potential explanation for the lack of effect of enalapril and losartan on collateral growth. The results demonstrate the capability of antioxidant therapies, including captopril, to reverse impaired collateral artery growth and the novel finding that components of the local renin angiotensin system are naturally suppressed in collaterals.


Assuntos
Transtornos do Crescimento/fisiopatologia , Hipertensão/fisiopatologia , Artérias Mesentéricas/crescimento & desenvolvimento , Estresse Oxidativo , Sistema Renina-Angiotensina , Animais , Masculino , Ratos , Ratos Endogâmicos SHR
18.
Anat Embryol (Berl) ; 211(5): 535-47, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16897012

RESUMO

The microvascular anatomy of the small intestine of metamorphosing tadpoles of the South African Clawed Toad, Xenopus laevis (Daudin) is studied from developmental stages 55 to 65 and in adults by scanning electron microscopy (SEM) of vascular corrosion casts (VCCs) and light microscopy. Up to stage 62, VCCs reveal a dense two-dimensional vascular network ensheating the intestinal tube, whose proximal portion forms a clockwise spiralling outer and its distal portion an anti-clockwise spiralling inner coil. Vessels of the intestinal network impose flat and run circularly to slightly obliquely. Locally, dense capillary plexus with small "holes" indicating ongoing intussusceptive microvascular growth (IMG) and vessel maturation, are present. The typhlosole, an invagination along the proximal portion of the small intestine, reveals a dense capillary bed with locally ongoing IMG. VCCs of stages 62/63 for the first time reveal a three-dimensional vascular bed with longitudinal intestinal folds of varying size and heights greatly enlarging the luminal exchange area of the intestinal tube. From stage 65 onwards, longitudinal intestinal folds undulate and, though smaller in size and less mature as indicated in VCCs by the presence of wider, sinus-like vessels with small "holes" interposed between, closely resemble the intestinal folds present in the small intestine of adult Xenopus. Our data suggest that maturation of the vascular pattern in the small intestine of X. laevis tadpoles takes place successively after stages 62-63, and growth during this period is preferentially by intussusception.


Assuntos
Intestino Delgado/irrigação sanguínea , Intestino Delgado/embriologia , Xenopus laevis/embriologia , Fatores Etários , Animais , Capilares/embriologia , Capilares/crescimento & desenvolvimento , Capilares/ultraestrutura , Artéria Celíaca/anatomia & histologia , Artéria Celíaca/embriologia , Artéria Celíaca/crescimento & desenvolvimento , Molde por Corrosão , Intestino Delgado/crescimento & desenvolvimento , Larva/anatomia & histologia , Larva/crescimento & desenvolvimento , Masculino , Artérias Mesentéricas/anatomia & histologia , Artérias Mesentéricas/embriologia , Artérias Mesentéricas/crescimento & desenvolvimento , Microscopia Eletrônica de Varredura , Xenopus laevis/crescimento & desenvolvimento
19.
Am J Physiol Heart Circ Physiol ; 291(2): H804-12, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16565305

RESUMO

Resistance artery narrowing and stiffening are key elements in the pathogenesis of essential hypertension, but their origin is not completely understood. In mesenteric resistance arteries (MRA) from spontaneously hypertensive rats (SHR), we have shown that inward remodeling is associated with abnormal elastic fiber organization, leading to smaller fenestrae in the internal elastic lamina. Our current aim is to determine whether this alteration is an early event that precedes vessel narrowing, or if elastic fiber reorganization in SHR arteries occurs because of the remodeling process itself. Using MRA from 10-day-old, 30-day-old, and 6-mo-old SHR and normotensive Wistar Kyoto rats, we investigated the time course of the development of structural and mechanical alterations (pressure myography), elastic fiber organization (confocal microscopy), and amount of elastin (radioimmunoassay for desmosine) and collagen (picrosirius red). SHR MRA had an impairment of fenestrae enlargement during the first month of life. In 30-day-old SHR, smaller fenestrae and more packed elastic fibers in the internal elastic lamina were paralleled by increased wall stiffness. Collagen and elastin levels were unaltered at this age. MRA from 6-mo-old SHR also had smaller fenestrae and a denser network of adventitial elastic fibers, accompanied by increased collagen content and vessel narrowing. At this age, elastase digestion was less effective in SHR MRA, suggesting a lower susceptibility of elastic fibers to enzymatic degradation. These data suggest that abnormal elastic fiber deposition in SHR increases resistance artery stiffness at an early age, which might participate in vessel narrowing later in life.


Assuntos
Animais Recém-Nascidos/fisiologia , Artérias/fisiologia , Tecido Elástico/fisiologia , Fibras Musculares Esqueléticas/fisiologia , Resistência Vascular/fisiologia , Animais , Artérias/citologia , Artérias/crescimento & desenvolvimento , Colágeno/metabolismo , Elastina/metabolismo , Técnicas In Vitro , Masculino , Artérias Mesentéricas/crescimento & desenvolvimento , Artérias Mesentéricas/fisiologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
20.
Neuropharmacology ; 50(2): 191-208, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16226282

RESUMO

This study aimed to examine the expression and function of P2 receptors of the rat tail and mesenteric arteries during maturation and ageing (4, 6 and 12 weeks, 8 and 24 months). Functional studies and receptor expression by immunohistochemistry revealed a heterogeneous phenotype of P2 receptor subtypes depending on artery age. The purinergic component of nerve-mediated responses in the tail artery was greater in younger animals; similarly responses to ATP and alpha,beta-meATP and the expression of P2X1 receptors decreased with age. Contractile responses to 2-MeSADP decreased with age, and were absent at 8 and 24 months; P2Y1 receptor expression followed this pattern. UTP-induced contractions and P2Y2 receptor expression also decreased with age. The mesenteric artery contracted to UTP, responses at 4 and 6 weeks were larger than at other ages although P2Y2 receptor expression did not significantly differ with age. 2-MeSADP induced relaxation of the mesenteric artery, responses being greatest at 6 weeks and decreased thereafter, which was mimicked by the P2Y1 receptor immunostaining. We speculate that the dramatic changes in expression of P2 receptors in the rat tail artery, compared to the mesenteric artery, during development and ageing are related to the role of the tail artery in temperature regulation.


Assuntos
Envelhecimento/fisiologia , Artérias/inervação , Artérias/fisiologia , Receptores Purinérgicos P2/fisiologia , Transdução de Sinais/fisiologia , Difosfato de Adenosina/análogos & derivados , Difosfato de Adenosina/farmacologia , Trifosfato de Adenosina/farmacologia , Agonistas alfa-Adrenérgicos/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Artérias/crescimento & desenvolvimento , Relação Dose-Resposta a Droga , Estimulação Elétrica , Imuno-Histoquímica , Masculino , Artérias Mesentéricas/crescimento & desenvolvimento , Artérias Mesentéricas/fisiologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/crescimento & desenvolvimento , Músculo Liso Vascular/fisiologia , Norepinefrina/farmacologia , Prazosina/farmacologia , Agonistas do Receptor Purinérgico P2 , Antagonistas do Receptor Purinérgico P2 , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/fisiologia , Transdução de Sinais/efeitos dos fármacos , Suramina/farmacologia , Cauda/irrigação sanguínea , Cauda/inervação , Tionucleotídeos/farmacologia , Uridina Trifosfato/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...