Introdução. A hiperativação nervosa simpática é característica marcante da insuficiência cardíaca. Estudos apontam alterações no controle ergorreflexo muscular (mecano e metaborreflexo) como mecanismos potenciais para explicar esta modificação autonômica. Os mecanorreceptores (fibras do grupo III), que são ativadas pelo aumento no tônus muscular e modulados por metabólitos da via das ciclooxigenases, encontram-se hipersensibilizadas na insuficiência cardíaca. Ao contrário, a sensibilidade dos metaborreceptores (fibras do grupo IV), que são ativados pelo acúmulo de metabólitos durante as contrações musculares e modulados pelos receptores TRPV1 e CB1, encontra-se diminuída na insuficiência cardíaca. Por outro lado, o treinamento físico tem se mostrado uma importante ferramenta no tratamento da insuficiência cardíaca. Ele reduz os níveis de atividade nervosa simpática muscular (ANSM) no repouso e durante o exercício em pacientes portadores desta síndrome. Dessa forma, neste estudo, nós testamos a hipótese de que o treinamento físico melhoraria o controle mecano e metaborreflexo da ANSM em pacientes com insuficiência cardíaca, e se essa melhora está associada às alterações na via das ciclooxigenases e na expressão dos receptores TRPV1 e CB1, respectivamente. Métodos. Pacientes com insuficiência cardíaca foram consecutivamente e aleatoriamente divididos em dois grupos: insuficiência cardíaca não treinado (ICNT, n=17) e insuficiência cardíaca treinado (ICT, n=17). A ANSM foi avaliada pela técnica de microneurografia e o fluxo sanguíneo muscular (FSM) pela pletismografia de oclusão venosa. A frequência cardíaca (FC) e a pressão arterial (PA) foram avaliadas por medida não invasiva a cada batimento (Finometer). Foi realizada biopsia muscular do vasto lateral para análise de expressão gênica. O treinamento físico aeróbio foi realizado em ciclo ergômetro, em intensidade moderada, por 40 minutos, três vezes por semana, durante 16 semanas. A sensibilidade mecanorreflexa foi calculada pelo delta absoluto entre o pico do exercício passivo, realizado na perna esquerda, e a média do registro basal. A sensibilidade metaborreflexa foi calculada pelo delta absoluto entre o 1º minuto de oclusão circulatória pós-exercício na perna esquerda e a média do registro basal. Resultados. O treinamento físico reduziu a ANSM e aumentou o FSM no repouso. O treinamento físico diminuiu significativamente as respostas de ANSM durante o exercício passivo no grupo ICT. As repostas de PA média também foram menores no grupo ICT quando comparado ao grupo ICNT. Não houve alterações significativas nas repostas de FC, PA sistólica, PA diastólica e FSM durante o exercício passivo no grupo ICT. Em relação à sensibilidade metaborreflexa, o treinamento físico aumentou expressivamente as respostas de ANSM no 1º minuto de oclusão circulatória no grupo ICT. As respostas de FC, PA e FSM não foram alteradas neste grupo. Não foram observadas alterações significativas nos controles mecano e metaborreflexo musculares no grupo ICNT. Além disso, o treinamento físico reduziu significativamente a expressão gênica da enzima COX-2 e do receptor EP4 e aumentou significativamente a expressão dos receptores TRPV1 e CB1 no grupo ICT. Não foram verificadas alterações significativas nas expressões gênicas do grupo ICNT. Conclusões. O treinamento físico normaliza os controles mecano e metaborreflexo da ANSM em pacientes com insuficiência cardíaca. Estas alterações podem estar associadas às alterações na expressão gênica da enzima COX-2 e receptor EP4, e dos receptores TRPV1 e CB1, respectivamente. Em conjunto, estes achados podem explicar, pelo menos em parte, a diminuição da atividade nervosa simpática e a melhora na tolerância aos esforços em pacientes com insuficiência cardíaca / Introduction. Sympathoexcitation is the hallmark of heart failure. Studies suggest changes in ergoreflex muscle control (mechanoreflex and metaboreflex) as potential mechanisms to explain this autonomic alteration in heart failure. Mechanoreceptors (group III fibers) that are activated by mechanical stimuli and modulated by cyclooxygenase pathway metabolites are hypersensitive in heart failure. In contrast, the sensitivity of metaboreceptors fibers (group IV) that are activated by increases in ischemic metabolites during muscle contractions and modulated by TRPV1 and CB1 receptors is blunted in heart failure. On the other hands, exercise training has been shown to be an important strategy in the treatment of heart failure. It reduces the levels of muscle sympathetic nerve activity (MSNA) at rest and during exercise in patients suffering of this syndrome. Thus, we tested the hypothesis that exercise training would improve the mechanoreflex and metaboreflex control of MSNA in heart failure patients. In addition, we investigated whether the improvement in the mechanoreflex and metaboreflex control is related to changes in the cyclooxygenase pathway and expression of TRPV1 and CB1 receptors, respectively. Methods. Patients with heart failure were consecutively and randomly divided into two groups: heart failure untrained (HFUT, n = 17) and heart failure exercise-trained (HFET, n = 17). MSNA was measured by microneurography technique and muscle blood flow (MBF) by venous occlusion plethysmography. Heart rate (HR) and blood pressure (BP) were assessed by noninvasive measure on a beat-to-beat basis (Finometer). Gene expression analysis was investigated by vastus lateralis muscle biopsy. Aerobic exercise training was performed on a cycle ergometer at moderate intensity, three 40-min session/wk for 16 weeks. Mechanoreflex sensitivity was evaluated by means the absolute difference in MSNA at peak passive exercise and baseline. Metaboreflex sensitivity was calculated by means the absolute difference in MSNA at 1st min after exercise period with muscle circulatory arrest and baseline. Results. Exercise training reduced MSNA and increased MBF. Exercise training significantly decreased MSNA responses during passive exercise. The mean BP response was lower in HFET group when compared to HFUT group. There were no significant changes in HR, systolic and diastolic BP and MBF responses during passive exercise in HFET group. Regarding metaboreflex sensitivity, exercise training significantly increased the MSNA responses at 1st minute of post exercise circulatory arrest. The responses of HR, BP and MBF were unchanged after exercise training. No significant changes were observed in mechanoreflex and metaboreflex control in the HFUT group. Furthermore, exercise training significantly reduced gene expression of COX-2 and EP4 receptor and significantly increased expression of TRPV1 and CB1 receptors. There were no significant changes in the gene expressions in the HFUT group. Conclusions. Exercise training improves mechanoreflex and metaboreflex control of MSNA in heart failure patients. These changes may be associated with changes in gene expression of COX-2 and EP4 receptor and TRPV1 and CB1 receptor, respectively. Together, these findings may explain, at least in part, the decrease in sympathetic nerve activity and the improvement in exercise tolerance in patients with heart failure

Ultraviolet radiation (UVR) in solar light is important for skin biology. It is involved in the development acute and chronic skin inflammation, aging and cancer, causing erythema, tanning and local or systemic immunosuppression. Omega-3 polyunsaturated fatty acids (n-3 PUFA) are considered anti- inflammatory and could reduce the damage caused by overexposure to UVR. Although, n-3 PUFA have been considered as photoprotective agents, their exact mechanisms of action is not completely understood. The aim of the work is to determine the effect of UVR and the n-3 PUFA eicosapentaenoic acid (EPA), or docosahexaenoic acid (DHA) on human skin cells (in vitro study), specifically on: cell viability, apoptosis and their metabolism through the cyclooxygenase and lipoxygenase pathways. Also, to study the cellular incorporation and effect of n-3 PUFA on the fatty acid profile of skin cells. A clinical study was undertaken to assess the incorporation of n-3 PUFA supplements in human skin. A clinical study was performed in 40 healthy women (active group) supplemented with 4g/day of EPA (70%) and DHA (10%) and 40 healthy women (placebo group) supplemented with 4g/day of glyceryl tricoprylate coprate (GTCC). After 3 months, both blood samples and skin punch biopsies were collected and analysed for fatty acids by gas chromatography (GC). HaCaT keratinocytes and 46BR.1N fibroblasts were cultured and treated with 10 and 50μM of either EPA, or DHA or oleic acid (OA) for 72h and exposed to 15 and 50 mJ/cm2. Cell viability was measured by the MTT assay and cell apoptosis by a colorimetric method, at 24h post UVR. Cells and culture media were analysed by GC and liquid chromatography tandem mass spectrometry (LC/ESI-MS/MS) to assess cellular fatty acids and production of eicosanoids. The clinical a study showed that in RBC saturated fatty acids (SFA) (44.27±7.43%) were the main fatty acid group followed by n-6 PUFA (29.61±5.53%). While in dermal tissue monounsaturated fatty acids (MUFA) (58.90±9.80%) was the main fatty acid group followed by SFA (27.06±6.78%). A significant increase in EPA, DHA and docosapentaenoic acid (DPA) was observed in RBC but only EPA was significantly increased in the dermis post n-3 PUFA supplementation. . The viability of HaCaT keratinocytes and 46BR.1N fibroblasts decreased post UVR and this was further reduced post PUFA treatment. Cell apoptosis increased when cells were exposed to UVR and further increased when cells were treated with EPA and DHA. . In HaCaT keratinocytes MUFA (54.22±8.82%) was the main fatty acid group followed by FAS (37.11±.9.16%), while SFA (51.94±8.68%) was the main group followed by MUFA (27.07±4.79) in 46BR.1N. Treated both cells with EPA and DHA showed significant increased in cellular EPA, DPA and DHA. 46BR.1N fibroblasts produced higher levels of prostaglandins (PG) compared to HaCaT keratinocytes: PGE2 and PGD2 were the main PG in both HaCaT (7.96±3.18 and 1.48±1.19 pg/million cell; respectively) and 46BR.1N with (44.2±23.00 and 17.1±9.71 pg/million cell; respectively). Significant increase in PGE1 and PGE2 occurred when cells were exposed to 15mJ/cm2 UVR. Treatment with n-3 PUFA decreased the level of PGE1 and PGE2, and increase production PGE3 at the baseline and post UVR. Both cell lines produced hydroxy fatty acids and the concentration of these mediators was higher in 46BR.1N than HaCaT. The concentrations of these mediators were significant increased post UVR: treatment with n-3 PUFA decreased the level of HODE and HETE, and increase production of HEPE and HDHA at baseline and post UVR. Overall, n-3PUFA treatment led to increases in the content of EPA and DHA on RBC, dermal tissue and human skin cell lines. EPA and DHA in skin cell lines appear to offer protection by increasing cellular apoptosis, decreasing inflammatory mediators specifically PGE2 and 12-HETE, and increasing anti-inflammatory mediators such as PGE3, 15-HEPE and 17-HDHA.

<p>Impaired endothelium-dependent vasodilation (EDV) is associated with atherosclerotic cardiovascular disease as well as several of its risk factors.</p><p>The aim of the present thesis was to investigate how lipids influence EDV in the vascular bed of the human forearm.</p><p>Apolipoprotein B was inversely associated with both EDV and endothelium-independent vasodilation (EIDV) in healthy subjects aged 20-69 years. HDL cholesterol was associated with the EDV to EIDV ratio (EFI). Small LDL particles and antibodies against oxidized LDL were not associated with endothelial vasodilatory function.</p><p>The EFI in young, healthy subjects was positively associated with alpha-linolenic acid proportion, but inversely associated with myristic acid in men only. Eicosapentaenoic acid was positively associated with EDV, whereas dihomo-gamma-linolenic acid was inversely associated with both EDV and EIDV in men. </p><p>Acute elevation of long-chain fatty acids with Intralipid^®/heparin infusion in young, healthy subjects impaired EDV after 2 h. This impairment could be prevented by co-infusing vitamin C, diclophenac or L-arginine. Acute elevation of both medium-chain and long-chain fatty acids during Structolipid^®/heparin infusion did not impair EDV.</p><p>An ordinary meal (34 E% fat) transiently attenuated EDV at 1 hour. No attenuation in EDV was observed after meals containing 20 and 3 E% fat. </p><p>These findings show that the endothelial vasodilatory function is associated with fatty acid profile in serum in the fasting state and during acute fatty acid elevation, as well as with apolipoprotein B and HDL cholesterol. Furthermore, lowering dietary fat content to 20 E% or less preserves endothelial vasodilatory function and might therefore protect against atherosclerosis.</p>

Impaired endothelium-dependent vasodilation (EDV) is associated with atherosclerotic cardiovascular disease as well as several of its risk factors. The aim of the present thesis was to investigate how lipids influence EDV in the vascular bed of the human forearm. Apolipoprotein B was inversely associated with both EDV and endothelium-independent vasodilation (EIDV) in healthy subjects aged 20-69 years. HDL cholesterol was associated with the EDV to EIDV ratio (EFI). Small LDL particles and antibodies against oxidized LDL were not associated with endothelial vasodilatory function. The EFI in young, healthy subjects was positively associated with alpha-linolenic acid proportion, but inversely associated with myristic acid in men only. Eicosapentaenoic acid was positively associated with EDV, whereas dihomo-gamma-linolenic acid was inversely associated with both EDV and EIDV in men. Acute elevation of long-chain fatty acids with Intralipid®/heparin infusion in young, healthy subjects impaired EDV after 2 h. This impairment could be prevented by co-infusing vitamin C, diclophenac or L-arginine. Acute elevation of both medium-chain and long-chain fatty acids during Structolipid®/heparin infusion did not impair EDV. An ordinary meal (34 E% fat) transiently attenuated EDV at 1 hour. No attenuation in EDV was observed after meals containing 20 and 3 E% fat. These findings show that the endothelial vasodilatory function is associated with fatty acid profile in serum in the fasting state and during acute fatty acid elevation, as well as with apolipoprotein B and HDL cholesterol. Furthermore, lowering dietary fat content to 20 E% or less preserves endothelial vasodilatory function and might therefore protect against atherosclerosis.

The dioxygenase-cytochrome P450 fusion proteins (DOX-CYP) comprise a heme-containing enzyme family that shares structural and catalytic properties with mammalian prostaglandin H (PGH) synthases. 7,8-Linoleate diol synthase (7,8-LDS) of Gaeumannomyces graminis was first characterized, and DOX-CYP enzymes are of mechanistic and biological interest. The growing number of fungal genome sequences has revealed DOX-CYP homologues in medically and economically important species. The aim of this thesis was to identify novel members of the DOX-CYP fusion protein family. The devastating rice pathogen Magnaporthe oryzae contains two DOX-CYP genes. The fungus synthesizes 7S,8S-dihydroxyoctadecadienoic acid (7,8-DiHODE) by dioxygenation of linoleic acid to 8R-hydroperoxyoctadecadienoic acid (8R-HPODE), and subsequent isomerisation to the diol. 7,8-LDS of M. oryzae was identified by gene deletion, but the infection and reproduction processes of the Δ7,8-LDS strain were not altered. A mutant with constitutive protein kinase A activity profoundly changed the oxygenation profile, possibly due to post-translational modification. The human pathogens Aspergillus fumigatus and A. clavatus contain three DOX-CYP, designated psi producing oxygenase A (ppoA), ppoB, and ppoC, and form three oxylipins: 5S,8R-DiHODE, 8R,11S-DiHODE, and 10R-hydroxyoctadecadienoic acid.  PpoA was identified as 5,8-LDS, and ppoC as 10R-DOX. The 8,11-linoleate hydroperoxide isomerase activity was reduced by two imidazole-containing P450 inhibitors, miconazole and 1-benzylimidazole. PpoB could not be linked to the biosynthesis of 8,11-DiHODE for the following reasons: First, the 8,11-hydroperoxide isomerase activity was retained in A. fumigatus ΔppoB strains. Second, the P450 domain of the deduced ppoB of A. clavatus lacks a heme-thiolate cysteine ligand, presumably essential for hydroperoxide isomerase activity. Linoleate 9R-DOX activities of Aspergillus terreus and Lasiodiplodia theobromae were discovered. 9R-HPODE was further converted into unstable allene oxides, as judged by the accumulation of their hydrolysis products, α- and γ-ketols. These allene oxide synthase activities were specific for 9R-hydroperoxides. The 9R-DOX and AOS were found to have unique characteristics. In conclusion, novel DOX-CYP enzymes were identified in human and plant pathogenic fungi. These enzymes might be involved in biological processes, and show interesting catalytic similarities to human PGH synthase and thromboxane synthase (CYP5A).

L’altération de la barrière hématoencéphalique (BHE) par les cellules tumorales et les cellules immunes circulantes peut mener à la neuroinflammation. Les cellules leucémiques promyélocytaires HL-60 sont un excellent modèle pour étudier et comprendre les mécanismes de signalisation moléculaires qui caractérisent le développement tumoral et métastatique. La cancérogenèse peut s’accompagner de modulations de l’expression de biomarqueurs tels que la cyclooxygénase-2 et la métalloprotéase-9. Les recherches décrites dans ce mémoire relatent l’analyse des biomarqueurs inflammatoires et invasifs régulés lors de la différenciation induite par le PMA des cellules HL-60 en macrophages. Le statut de différenciation cellulaire pourrait avoir un impact sur les gènes cibles de la voie NF-κB. Nous émettons l’hypothèse que le PMA active la voie NF-κB et que cette signalisation peut être renversée par l’(-)-épigallocatéchine-gallate (EGCG). En effet, une régulation à la hausse de l’expression de plusieurs gènes combinée à la diminution de l’expression d’IκB mettent en évidence l’implication de la voie NF-κB dans l’activation des mécanismes pro-inflammatoires et pro-invasifs. Les mêmes observations sont faites dans les cellules différenciées appelées «macrophages-like». L’EGCG, un polyphénol dérivé du thé vert, a un potentiel chimiopréventif. Il est capable d’inhiber la signalisation moléculaire passant par la voie NF-κB dans les cellules HL-60 traitées simultanément par l’EGCG et le PMA, mais pas dans les cellules «macrophages-like». Cette différence peut s’expliquer par une modulation de l’expression du récepteur de surface cellulaire de l’EGCG, le récepteur à la laminine de 67 kDa, et de son précurseur de 37 kDa. Collectivement, nos résultats montrent que le statut de différenciation des cellules promyélocytaires HL-60 concorde avec l’activation des mécanismes favorisant le développement d’un cancer et des métastases. Cet effet peut être prévenu par l’utilisation d’agents naturels tel l’EGCG. Le ciblage de biomarqueurs liés au statut de différenciation des cellules tumorales impliquées dans la perturbation de la barrière hématoencéphalique qui cause la neuroinflammation permettrait l’avancement des connaissances dans la prévention de la cancérogenèse. / Blood-brain barrier (BBB) disruption by circulating tumor and immune cells leads to secondary inflammatory infections. Promyelocytic HL-60 cells represent an excellent model to study and to get a better understanding of the molecular signaling mechanisms involved in carcinogenesis and metastasis. The research described in this thesis shows the analysis of several inflammatory and invasive biomarkers regulated during PMA-induced differentiation of promyelocytic HL-60 cells into macrophages. Carcinogenesis involves some modifications in the expression of biomarkers such as cyclooxygenase-2 and matrix metalloprotease-9. The differentiation status could have an impact on the NF-κB signaling pathway that regulates the target genes, given that these target genes expression varies during cell differentiation. We hypothesize that the activation of the NF-κB pathway by PMA can be reverse by (-)-epigallocatechin-gallate (EGCG). Indeed, the up-regulation of downstream genes combined with the down-regulation of IκB expression showed the significant implication of the NF-κB signaling pathway to activate pro-inflammatory and pro-invasive mechanisms linked to carcinogenesis. The same evidence exhibits in the differentiated cells called «macrophages-like». Moreover, the green tea polyphenol, EGCG, shows chemopreventive property since it better inhibited NF-κB signaling in cells treated simultaneously with EGCG and PMA compared to the «macrophages-like». This difference could be due, in part, to the down-regulation of the 67 kDa laminin receptor, known to be the non-integrin membrane receptor for EGCG. All together, our results suggest that the differentiation status of promyelocytic cells is linked to the activation of mechanisms involved in carcinogenesis and metastasis. These phenomena can be prevented by using natural agents such as EGCG. Targeting the specific biomarkers linked to the differentiation status of tumor cells and involved in the disruption of the BBB may help reduce secondary neuroinflammation and enable the advancement of knowledge towards carcinogenesis prevention.

Vasomotor tone is largely maintained by sympathetic nerves, myogenic reactivity and key local and circulating hormones. Acting together, these factors ensure moment-to-moment adjustments of net vascular tone required to maintain hemodynamic stability. In rat mesenteric small veins (MSV) and arteries (MSA), we investigated the contribution of the endothelium, L-type voltage operated calcium channels (L-VOCCs), PKC and Rho kinase to myogenic reactivity. The interaction of myogenic reactivity with norepinephrine (NE), endothelin-1 (ET-1), and sympathetic nerve activation was also investigated under conditions of changing transmural distending pressure. We also evaluated the relative contribution of alpha adrenergic (α-A) and endothelinergic receptors to NE and ET-1 contractile responses, respectively. Additionally, the effects of changing transmural pressure on endothelial dilator function of MSV were examined. Myogenic reactivity was not altered by nitric oxide synthase (NOS) inhibition or endothelium removal in both vessels. L-VOCCs blockade completely abolished arterial tone, while only partially reducing venous tone. PKC and Rho kinase inhibitors largely abolished venous and arterial myogenic reactivity. Increasing transmural pressure did not alter NE, ET-1, and bradykinin responses, but it significantly reduced neurogenic contractions. MSV were more sensitive to NE, ET-1 and sympathetic nerve activation compared with corresponding arteries. α-A and ET-1 receptor agonist and antagonist application revealed the participation of α1-A and ETA receptors in NE and ET-1 contractile responses, respectively. α2-A and ETB receptors appeared to mediate NE and ET-1 responses in MSV, respectively. Bradykinin induced-vasodilation was mainly reduced by NOS inhibition, and BKCa and SkCa blockade. These results suggest that myogenic factors are important contributors to net venous tone in MSV; PKC and Rho kinase activation are important to myogenic reactivity in both vessels, while L-VOCCs play a limited role in the veins versus the arteries; mesenteric veins maintain an enhanced sensitivity to NE, ET-1 and sympathetic nerve activation compared to the arteries with neurogenic contractions being affected by transmural pressure elevations; α1-ARs and ETA are the predominant receptors mediating contractile responses to NE and ET-1, respectively, with functional evidence indicating the presence of α2-ARs and ETB receptors in MSV; and venous endothelial dilator function is not affected by an elevation of transmural pressure. / Natural Sciences and Engineering Research Council of Canada (NSERC). Libyan Ministry of Education and Scientific Research.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2005. / Härtill 4 uppsatser.

Thesis (Ph.D. in Pharmacology) -- University of Colorado Denver, 2008. / Typescript. Includes bibliographical references (leaves 117-147). Free to UCD Anschutz Medical Campus. Online version available via ProQuest Digital Dissertations;

A doença periodontal é caracterizada por alterações inflamatórias, como vermelhidão e edema da margem gengival, sangramento provocado, alterações no contorno gengival e perda óssea alveolar. Evidências recentes sugerem que o fator de crescimento endotelial vascular (VEGF) pode ser um mediador importante na doença periodontal inflamatória. Portanto, este trabalho teve como objetivos avaliar durante a progressão da doença periodontal inflamatória induzida experimentalmente em ratos: 1) o efeito do meloxicam, inibidor preferencial da COX-2, na perda óssea alveolar; 2) a cinética de expressão de RNAm para COX-2, VEGF, VEGFR-1 e VEGFR-2; e 3) a cinética de expressão da proteína VEGF. Cento e vinte (120) ratos foram aleatoriamente divididos em: grupo 1 (sem tratamento com meloxicam) e grupo 2 (tratados com meloxicam). Ligaduras de fio de seda foram colocadas na margem gengival do primeiro molar inferior direito de todos os ratos. O grupo 2 foi tratado por 3, 7, 14 e 30 dias com meloxicam (3 mg/kg/dia, via intraperitoneal) e o grupo 1 foi usado como controle. As técnicas utilizadas para as análises foram: análise microscópica, RT-PCR, Western Blot e imunohistoquímica. Os resultados foram submetidos à análise de Correlação de Pearson, Análise de Variância (ANOVA), seguida do teste de Tukey, sendo adotado nível de significância de 5%. Observou-se, neste estudo, que o meloxicam foi efetivo em diminuir a perda óssea alveolar nos tecidos periodontais em todos os períodos de indução da doença periodontal. Experimentos de RT-PCR revelaram correlação positiva da cinética de expressão de RNAm para COX-2 e VEGF nos tecidos gengivais afetados pela doença periodontal inflamatória (R=0,80). A expressão de RNAm para VEGF na doença periodontal inflamatória, no período de 14 dias, diminuiu no grupo de animais tratados com meloxicam, mostrando diferença estatisticamente significativa quando comparado com os animais não tratados (p=0,023). Não houve diferença significativa na expressão de RNAm para os receptores VEGFR-1 e VEGFR-2 no tecido gengival em nenhum dos períodos de indução da doença periodontal. Nos experimentos de Western Blot houve tendência de menor expressão da proteína VEGF na doença periodontal inflamatória no período de 14 dias nos animais tratados com meloxicam (p=0,08). Em experimentos de imunohistoquímica foi detectado aumento da expressão da proteína VEGF nos tecidos afetados pela doença periodontal em todos os períodos estudados, bem como diminuição da expressão desta proteína nos tecidos periodontais dos animais tratados com meloxicam. Portanto, a análise conjunta dos dados sugere importante participação do VEGF na doença periodontal inflamatória induzida experimentalmente em ratos e o meloxicam, inibidor preferencial da COX-2, pode modificar a progressão da doença periodontal neste modelo experimental por diminuir a perda óssea e a expressão de VEGF. / Inflammatory periodontal disease is characterized by alveolar bone loss and inflammatory changes in the periodontal tissues, which become hemorrhagic and edematous. However, there is little information concerning the biologic mechanisms which may produce these changes. Vascular endothelial growth factor (VEGF) is a macromolecule of importance in inflammation. The aims of this study were to investigate the presence of VEGF during progression of periodontal disease, and to evaluate the effect of a preferential COX-2 inhibitor, meloxicam, on the alveolar bone loss and VEGF expression in experimentally induced periodontitis. One hundred and twenty (120) Wistar rats were randomly separated into two groups [group 1 (no treatment with meloxicam) and group 2 (treatment with meloxicam)]. Silk ligatures were placed at the gingival margin level of the lower right first molar of all rats. Group 2 was treated for 3, 7, 14 and 30 days with meloxicam (3 mg/kg/day, intraperitoneal) and the group 1 was used as control. The expression of VEGF was assessed by RT-PCR, Western Blot and immunohistochemical analysis. Alveolar bone loss was determined by microscopic analysis. The results were submitted to the analysis of Correlation Coefficient by Pearson, Analysis of Variance (ANOVA), and Tukey\'s post test (p<0.05). A reduction of the alveolar bone resorption was observed in the meloxicam treated group (2), as compared with the control group (1) in all periods studied. There was a positive correlation between COX- 2 mRNA and VEGF mRNA in the gingival tissue with periodontal disease (R=0.80). VEGF mRNA expression was significantly lower in rats treated with meloxiam after 14 days (p=0.023). No difference in the expression of VEGFR-1 mRNA and VEGFR-2 mRNA was observed for all the periods studied. VEGF protein expression was significantly higher in diseased sites as compared with healthy sites (p<0.05). After 14 days lower VEGF protein expression in rats treated with meloxicam was detected (p=0.08). Altogether these data suggest an important participation of VEGF in the progression of periodontal disease, and the systemic therapy with meloxicam, preferential COX-2 inhibitor, can modify the progression of experimentally induced periodontitis in rats by reducing the alveolar bone loss and the VEGF expression.