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The mechanical function of the uterine cervix is critical for a healthy pregnancy. During pregnancy, the cervix undergoes a significant remodeling from a mechanical barrier into a compliant structure to allow for a successful delivery. A too early or too late cervical softening will lead to spontaneous preterm births (sPTB) or dystocia. PTB is a leading cause of neonatal death, affecting 15 million newly born babies each year around the world. According to CDC, the rate of PTB increases in recent years. Dystocia increases the risk to both mother and newborn babies, leading to neonatal asphyxia, neonatal infection, uterine rupture, or other dangerous sequelae. Therefore, it is significant to have a better correlation of the mechanical properties change and the biological remodeling process of the cervix during pregnancy. This thesis will focus on (1) mechanical experiments of the human cervix, and (2) the development of a material constitutive model for cervix to characterize the complex microstructure-related mechanical property of the cervix. In this thesis, a spherical indentation test was designed and conducted on human cervical samples sliced perpendicular to the axial direction, to characterize the compressive mechanical behavior of the human cervix. A uniaxial tensile was designed and conducted on the strip samples cut along and perpendicular to the preferential fiber direction from the indentation samples, to characterize the tensile mechanical behavior of the cervix. Based on the detailed experimental investigation, a nonlinear time-dependent anisotropic microstructure-inspired constitutive model has been developed. The basic idea of the model is that the mechanical behavior of the human cervix can be decomposed into an equilibrium and a time-dependent part, and the tension and compression mechanical behaviors are caused by disparate mechanisms. Specifically, the collagen fibrous network plays a major role in the tensile mechanical response, while proteoglycans (PGs), glycosaminoglycans (PGs),, and liquid cause the compressive mechanical response. The tensile time-dependent mechanical behavior of the human cervix is mostly attributed to the interactions between the collagen fiber and other components, while the compressive time-dependent mechanical behavior is mainly attributed to the porous effect. The equilibrium and time-dependent mechanical responses have been well captured using the model, and the results reveal the connection between the ECM microstructure remodeling and mechanical properties change during pregnancy.

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The overall focus of this dissertation is on how chronic shear stress alters the synthesis and secretion of important regulatory molecules by endothelial cells. Our hypothesis was that inclusion of chronic pulsatile shear stress in our model would lead to changes in endothelial cell release of regulatory molecules. We distinguished between high arterial shear stresses and low venous shear stresses and used static cell cultures as reference. The first part of this research thus entailed the complete characterization of the flow dynamics in our experimental biomechanical model. Cell stretching can have a physiological effect on endothelial cells; hence we implemented a laser based optical technique for real time strain measurement of the growth fibers used in our culture system, and found that no significant strains were occurring during shear treatment. After characterization of the mechanical environment of the cells, we focused the scope of our research on metabolism of proteoglycans and insulin-like growth factor-I (IGF-I) and related IGF binding proteins (IGFBPs) in bovine aortic endothelial cells cultured under chronic pulsatile shear. We found that shear stress increased the release of proteoglycans and significantly altered proteoglycans distribution. We also found that there was an inverse relationship between the shear level treatment used to obtain the purified proteoglycans from endothelial cells and their potency in inhibiting coagulation. IGF-I release and message (IGF-I mRNA) was decreased at high shear stress compared to low shear stress. Further, the levels found under shear were significantly greater than those observed in the static cell culture model. IGFBPs released were also significantly increased by shear. This research thus establishes a link between chronic pulsatile shear stress and the metabolism of both primary (IGF-I) and secondary (IGFBPs, proteoglycans) regulators of vascular cell activity. The improved realism of our experimental biomechanical model has proved to be a valuable tool in improving the relevance of this study to vascular research. Ultimately, this research calls for further investigation in the molecular mechanisms underlying the phenomenological effects documented, which may help in understanding fundamental aspects in cardiovascular disease and its link to hemodynamics but our work is an important first step. / Ph. D.

A cicatrização do tendão é um complexo processo que envolve uma variedade de moléculas reguladoras. Como exemplos temos os fatores de crescimento positivamente correlacionados com a expressão de genes responsáveis pela síntese da matriz extracelular, bem como os proteoglicanos que atuam como organizadores dos tecidos capazes de modular o crescimento e a maturação celular de tecidos especializados. No intuito de reparar o tendão com lesão existem várias opções de tratamento, mas nenhuma tem sido relatada como plenamente eficaz. Sendo assim, na busca de tratamentos regenerativos e não apenas reparativos, o objetivo deste trabalho foi investigar a influência do plasma rico em plaquetas (PRP) no processo de cicatrização do tendão flexor digital superficial de equinos, utilizando-se deste tratamento isoladamente ou associado ao laser terapêutico. Com essa finalidade, 26 membros torácicos de equinos foram distribuídos aleatoriamente em quatro grupos distintos: o grupo 1 (G1) foi composto por oito membros torácicos sadios provenientes de cadáveres frescos; no grupo 2 (G2) em seis membros foi induzida a tendinite, sem a realização de qualquer tipo de tratamento; no grupo 3 (G3) a tendinite também foi induzida em seis membros, os quais receberam o tratamento com o PRP; e no grupo 4 (G4) a tendinite foi induzida em seis membros torácicos que receberam o tratamento com o PRP associado ao laser terapêutico. Os animais foram avaliados clinicamente e ultrassonograficamente. Já as amostras do tecido tendíneo, obtidas por biópsia guiada por ultrassom, foram avaliadas por imunoistoquímica quanto a presença dos proteoglicanos: decorim, biglicam, fibromodulim e agrecam, Nessas amostras também foi realizada a análise da birrefringência do colágeno. Na avaliação clínica verificou-se que o grupo G4 foi o único que não mais apresentou sensibilidade à palpação no local da lesão ao término do experimento. Já na avaliação ultrassonográfica, os tendões dos membros torácicos dos grupos G3 e G4 que receberam os tratamento com PRP demonstraram melhora na ecogenicidade tanto do tendão como da lesão. Além disso, os tendões do grupo G4 apresentaram melhora no paralelismo das fibras de colágeno. Na avaliação imunoistoquímica os resultados demostraram que o biglicam, o fibromodulim e o agrecam tiveram sua expressão aumentada nas amostras do grupo G4 tratados com a associação PRP e laser quando comparados com as amostras do tendão hígido do grupo G1. Já no grupo G2 observou-se apenas o aumento da expressão de agrecam em relação ao G1. Na análise da birrefringência do colágeno o maior valor de retardo óptico (OR) foi apresentado também nas amostras do grupo tratado com a associação do PRP e laser (G4). Durante o processo de regeneração de um tendão lesado há uma tendência para o aumento dos valores de OR, o que representa uma melhora na organização do colágeno. Provavelmente, o laser foi capaz de produzir um aumento na síntese de colágeno e uma melhor agregação e alinhamento das fibras de colágeno. Assim, concluímos que o tratamento com PRP associado ao laser demonstrou melhora clínica, ultrassonográfica, de birrefringência e na expressão de proteoglicanos da matriz extracelular, o que não ocorreu quando utilizado isoladamente. / Tendon healing is a complex process involving a variety of regulatory molecules. Growth factors are a family of such molecules; and their presence is positively correlated with the expression of genes responsible for extracellular matrix synthesis. Proteoglycans more than extracellular matrix components are tissue organizers capable of modulating cell growth and maturation in specialized tissues. In order to repair the tendon injury there are several treatment options, but none has been reported as fully effective. In this scenario, regenerative approaches are currently preferred over reparative therapeutic procedures. Therefore, the aim of this study was to investigate the influence of platelet-rich plasma (PRP) in the healing of the equine superficial digital flexor tendon, using this treatment, alone or associated with the laser therapy. For this purpose, 26 equine forelimbs were randomly divided into four groups: group 1 (G1) consisted of eight healthy forelimbs from fresh cadavers; in group 2 (G2), tendinitis was induced in six forelimbs, without performing any type of treatment; in group 3 (G3), tendinitis was also induced in six forelimbs which received PRP treatment; and in group 4 (G4), tendinitis was induced in six forelimbs that received treatment with PRP associated with laser therapy. All animals were evaluated clinically and sonographically. Additionally, tendon tissue samples were obtained by ultrasound-guided biopsy, and assessed by immunohistochemistry to determine proteoglycans expression (decorin, biglycan, fibromodulin and aggrecan). These samples were further analyzed for collagen organization through birefringence. In the clinical evaluation, only G4 animals had absent painful response to direct digital palpation at the end of the experiment. During sonographic evaluation, it was observed that tendons from groups G3 and G4, that received the treatment with PRP, demonstrated improvement in both tendon and lesion echogenicity. Furthermore, tendons from the G4 group showed improvement in axial alignment of collagen fibers. The results showed an increase in biglycan, fibromodulin and aggrecan expression at immunohistochemical evaluation of G4 samples, when compared with healthy tendon samples (G1). In tendons from the G2 group only an increased aggrecam expression compared to G1 was observed. Though the analysis of the collagen birefringence, the highest value of optical retardation (OR) was also presented in the samples of the group treated with the combination of PRP and laser (G4). During the regeneration process of an injured tendon, there is a trend to increase OR values, which represents an improvement of the collagen organization. Probably, the laser was able to induce an increased synthesis and a better aggregation and alignment of collagen. So, we conclude that the animals treated with PRP associated with laser therapy improved clinically and sonographically. Moreover, this treatment improved the arrangement of collagen fibril and enhanced the proteoglycans expression in the extracellular matrix, what did not occur when PRP treatment was used alone.

O quelóide é um processo cicatricial, com freqüência aumentada em regiões com maior tensão na pele ou onde a pele é mais espessa, caracterizado por exceder-se além dos limites da lesão que o originou e pela tendência à recidiva após sua ressecção. Ambos os sexos são acometidos, com maior incidência entre a primeira e a terceira década de vida e em indivíduos de etnia negra. A relação familial é sugerida como herança autossômica dominante. O quelóide apresenta características moleculares distintas da pele normal envolvendo uma variedade de sinalizações ainda pouco compreendidas e um aumento da expressão de componentes da matriz extracelular, como o colágeno, os glicosaminoglicanos e os proteoglicanos. Este estudo analisou a expressão gênica dos proteoglicanos de superfície celular sindecam-2 e sindecam-4 e dos de matriz extracelular decorim e versicam no tecido derivado de quelóide de indivíduos não tratados em comparação com a pele clinicamente normal. Participaram desse estudo 10 indivíduos portadores de quelóides (grupo Q) e 10 indivíduos não portadores dessa cicatriz (grupo N). A expressão gênica dos proteoglicanos foi amplificada pela reação em cadeia da polimerase por transcrição reversa e analisada através de eletroforese em gel de agarose. Foi realizada a localização dos proteoglicanos nos tecidos através de reação imunohistoquímica com anticorpos para os sindecans-2 e 4. Os grupos foram comparados pelo teste t de Student. Os proteoglicanos de superfície celular mostraram-se aumentados no grupo Q (93% para o sindecam-2 e 152,5% para o sindecam-4) em comparação com o grupo N (P<0,01). Não foram observadas diferenças significativas para os proteoglicanos de matriz extracelular entre os dois grupos. A análise imunohistoquímica mostrou uma distribuição marcante dos sindecans-2 e 4 no componente epitelial, conectivo, vascular e nervoso de toda a casuística. Concluímos que o quelóide apresenta aumento significativo da expressão gênica de sindecam- 2 e sindecam-4, mas não apresenta aumento significativo da expressão gênica de decorim e versicam, em relação à pele normal. / Keloid is a cicatricial process, with frequency increased in regions with bigger tension in the skin or where the skin is thicker, characterized for exceeding beyond the limits of the injury that originated it and for the tendency to relapse after its ressection. Its occurs in both genders, with bigger incidence between the first and the third decade of life and in individuals of black ethnia. The familial relation is consistent with an autosomal dominant inheritance. The keloid presents distinct molecular characteristics of the normal skin involving a variety of still little understood signallings and an increase of the expression of components of the extracellular matrix, as the collagen, the glicosaminoglycans and the proteoglycans. This study analyzed the gene expression of the proteoglycans of cell surface syndecan-2 and syndecan-4 and the ones of extracellular matrix decorin and versican in the keloid tissue from not treated individuals in comparison with the normal skin. Tissue samples was obtained from 10 individuals with keloid (Q group) and 10 individuals with normal skin (N group). The gene expression of the proteoglycans was amplified by reverse transcription polymerase chain reaction and analyzed through agarose gel electrophoresis. The localization of the proteoglycans in the tissues was performed through immunohistochemical reaction using panels of antibodies for syndecans-2 and 4. The groups was compared by the Student?s t test. The proteoglycans of cell surface revealed increased in Q group (93% for sydecan-2 and 152,5% for syndecan-4) in comparison with N group (P<0,01). Significant differences for the proteoglycans of extracellular matrix between the two groups was not observed. The immunohistochemical analysis showed a major distribution of syndecans-2 and 4 in epithelial, connective, vascular and neural components in both groups. We conclude that keloid reveal significant increase of the gene expression of syndecan-2 and syndecan-4, but does not present significant increase of the gene expression of decorin and versican, in relation to the normal skin.

Les protéoglycanes (PGs) sont des protéines présentes au niveau de la matrice extracellulaire et à la surface des cellules. Ils sont constitués d’une protéine sur laquelle sont attachées des chaînes de glycosaminoglycanes. Ils jouent un rôle essentiel dans plusieurs processus biologiques. Des mutations au niveau des gènes codant pour la protéine porteuse ou les enzymes impliquées dans la biosynthèse des GAGs sont associées à plusieurs syndromes et pathologies chez l’homme. L’initiation de la synthèse des GAGs est catalysée par la xylosyltransférase I (XT-I). La XT-I joue un rôle clé dans la régulation de la synthèse des PGs au niveau du cartilage et il a été montré récemment que les mutations hypomorphiques de la XT-I sont associées au syndrome du Desbuquois de type II (DBQD2) caractérisé par des anomalies squelettiques (ostéochondrodysplasie). Afin d’élucider le rôle de la XT-I dans le développement ostéoarticulaire, nous avons généré une souris transgénique conditionnelle Col2α1-CreERTM ;XylT1flox/flox permettant l’invalidation de la XT-I au niveau du cartilage. De façon intéressante, l’invalidation de la XT-I induit des anomalies du développement ostéoarticulaire caractérisées par un nanisme important et des défauts des éléments squelettiques. Des études histologiques et la microscopie SHG (génération de seconde harmonique) de la plaque de croissance ont permis de montrer l’importante de la XT-I dans la formation de la matrice extracellulaire (MEC), la fibrillation du collagène II, la maturation des chondrocytes et leur organisation en colonne dans la plaque de croissance. L’analyse des mécanismes moléculaires impliqués indique la perturbation de la voie de signalisation du TGF-β dans la plaque de croissance. D’autre part, des études histomorphométriques et histologiques des os ont révélé que la déficience en XT-I entraîne une accélération du processus d’ossification avec une stimulation de l’activité des ostéoclastes au niveau de l’os spongieux conduisant à une résorption osseuse importante et à une ossification accrue de l’os cortical. Ces travaux ont permis de révéler le rôle de la XT-I dans le développement ostéoarticulaire et dans le maintien de l’homéostasie du cartilage et du tissu osseux et ont mis en évidence le rôle de la voie du TGF-β dans les anomalies du développement. Ces travaux ouvrent également la voie pour le développement de thérapeutiques potentielles pour le traitement des patients atteints du syndrome de Desbuquois type II / Proteoglycans (PGs) are proteins present in the extracellular matrix and on the surface of cells. They consist of a protein to which chains of glycosaminoglycans (GAGs) are attached. PGs play an essential role in many biological processes and in the homeostasis of different tissues including cartilage, bone and skin. Mutations in the genes encoding PG core proteins or the enzymes involved in GAG biosynthesis are associated with several syndromes and pathologies in human. Initiation of GAG synthesis is catalyzed by xylosyltransferase I (XT-I). XT-I plays a key role in the regulation of the synthesis of PGs in cartilage and it has been shown recently that hypomorphic mutations of XT-I are associated with the Desbuquois syndrome type II (DBQD2), characterized by skeletal abnormalities (osteochondrodysplasia). To elucidate the role of XT-I in skeletal development, we generated a conditional transgenic mouse, Col2α1-CreERTM; XylT1flox/flox allowing the invalidation of XT-I gene in the cartilage. Interestingly, the invalidation of XT-I induces skeletal developmental abnormalities characterized by significant dwarfism, and defects in many skeletal elements. Histological studies and SHG microscopy (second harmonic generation) of the growth plate showed the importance of XT-I in extracellular matrix formation, fibrillation of collagen type II, maturation of chondrocytes and their organization in column in the growth plate. The analysis of the molecular mechanisms involved indicates the disruption of the TGF-β signaling pathway in the growth plate. On the other hand, histomorphometric and histological studies of the bones revealed that the XT-I deficiency causes an acceleration of the ossification process with a stimulation of the osteoclasts activity in spongy bone leading to bone resorption, and increased ossification of the cortical bone. This work revealed the role of XT-I in skeletal development and in the maintenance of cartilage and bone homeostasis and highlighted the role of the TGF-β pathway in developmental abnormalities. This work also paves the way for the development of potential therapeutics for the treatment of patients with Desbuquois syndrome type II

Introdução: Ratos com diabetes induzido por estreptozotocina (STZ) apresentam alterações nos proteoglicanos Sindecan-4 e Glipican-1 no tecido cardíaco concomitantes à instalação da disfunção diastólica, evento precoce que culmina na cardiomiopatia diabética. O uso de resveratrol (RSV) em modelos animais foi capaz de melhorar a função cardíaca e o controle autonômico. Espera-se que o tratamento com esse flavonoide atue nos níveis alterados dos proteoglicanos em animais diabéticos. Objetivo: Avaliar o efeito do RSV nos parâmetros cardiovasculares e na expressão dos proteoglicanos no músculo cardíaco. Materiais e Métodos: Foram avaliados ratos Wistar machos, com doze semanas de vida, divididos em 4 grupos: controle (C, N=8); controle + RSV (CR, N=8); diabetes STZ + nicotinamida (D, N=8) e diabetes STZ + nicotinamida + RSV (DR, N=8). Foram dosados os níveis séricos de glicose, de triglicérides e foi feito o teste de resistência à insulina. Registros diretos das curvas de pressão arterial foram realizados para a análise da variabilidade da frequência cardíaca (VFC) e variabilidade da pressão arterial sistólica (VPAS) no domínio do tempo e da frequência. A sensibilidade barorreflexa foi avaliada por meio de drogas vasoativas e a função cardíaca foi avaliada por ecocardiografia de alta resolução. A localização das proteínas no tecido cardíaco foi feita por imunohistoquímica. Análise estatística utilizada: ANOVA post test Student Newman-Keuls. p < 0,05. Resultados: O peso corporal dos grupos C e CR aumentou significativamente do inicio ao final do protocolo, enquanto os grupos D e DR mantiveram seu peso inicial. A concentração de glicose sérica e dos triglicerídeos, os grupos C e CR não demonstraram diferença ao longo do protocolo, enquanto os grupos D e DR demonstraram significante aumento ao final do protocolo. Os valores de concentração de insulina, do teste de tolerância à insulina e do índice de Lee foram menores nos grupos D e DR quando comparados aos grupos C e CR. A pressão arterial sistólica foi menor nos grupos diabéticos quando comparado aos grupos controles (C e CR) o mesmo acontecendo para os valores da frequência cardíaca. A pressão arterial diastólica apresentou valores semelhantes entre os grupos C e CR e o grupo DR, somente o grupo D apresentou queda quando comparado aos outros três grupos, a pressão arterial media apresentou esse mesmo comportamento. Não foram observadas diferenças para a sensibilidade barorreflexa tanto para a resposta bradicárdica como para a resposta taquicárdica entre os grupos. Nas avaliações da VFC foi observado o aumento do Intervalo de Pulso (IP) nos grupos D e DR quando comparados aos grupos C e CR, mas foram semelhantes entre os grupos controles e diabéticos (C vs. CR e D vs. DR, respectivamente). Na VPAS os grupos D e DR apresentaram diminuição tanto no desvio padrão (DP PAS) quanto na variância (VAR PAS) quando comparados aos grupos C e CR, não houve diferença entre os grupos controles e diabéticos (C vs. CR e D vs. DR, respectivamente). A disfunção diastólica foi detectada no grupo D. A expressão das proteínas Glypican-1 e Syndecan- 4, foram significantemente maiores no grupo D quando comparada aos demais grupos e menos expressas no grupo DR quando comparada aos demais grupos. Conclusões: A administração de RSV reverteu tanto alterações morfológias como a função cardíaca global que voltou a apresentar valores muito próximos aos valores de normalidade, sem alterar as condições hemodinâmicas e autonômicas / Introduction: Streptozotocin-induced rats model show changes in proteoglycans sindecan-4 and glipican-1 in cardiac tissue concomitantly with installation of diastolic dysfunction, which is an early event that culminates in diabetic cardiomyopathy. The use of resveratrol (RSV) in animal models showed the improvement of cardiac function and autonomic control. It is expected that the treatment with this flavonoid act on altered levels of proteoglycans in diabetic rats. Objective: To evaluate the effects of resveratrol in cardiovascular parameters and the expression of proteoglycans in cardiac muscle. Material and Methods: Male Wistar rats (12 weeks old) were allocated into 4 groups: control (C, N=8), controle+RSV (CR, N=8), Diabetes STZ + nicotinamide (D, N=8) and diabetes STZ+ nicotinamide + RSV (DR, N=8). Serum levels of glucose, insulin resistance test and triglycerides were measured in order to evaluate diabetes. Arterial blood pressure records were measured in order to analyze the heart rate variability (HRV) and systolic blood pressure variabilities in frequency and time domain. The baroreflex sensivity was evaluated by vasoactive drugs infusion and the evaluation of cardiac function by high resolution echocardiography. The location of the proteins in the heart tissue was performed by immunohistochemistry. Statistics and performed analysis used: ANOVA post test Student Newman-Keuls. p < 0,05. Results: Our results showed that the body weight of groups C and CR increased significantly from the beginning to the end of the protocol, while the groups D and DR continued to have the initial weight. Regarding serum glucose concentration and triglycerides, there were no statistically significant differences between group C and CR while the group D and DR increased significantly at the end of the protocol. The values of insulin concentration, insulin tolerance test and the Lee index were lower in groups D and DR when compared to groups C and CR. The hemodynamic parameters demonstrated that systolic blood pressure was lower in diabetic groups when compared to control groups (C and CR) as well as the heart rate values. Interestingly, diastolic blood pressure showed similar values between groups C, CR and group DR. The group D decreased its diastolic blood pressure when compared to the other groups, as well as the blood pressure mean. There were no significant differences either to baroreflex sensivity, bradicardiac response and tachycardia between both groups. The evaluation of heart rate variability (HRV) showed an increase of pulse interval (PI) in groups D and DR when compared to groups C and CR. The evaluation of systolic blood pressure variability of the groups D an DR showed a decrease in both the standard deviation (SD PAS) and variance when compared to groups C and CR and there were no differences between the diabete groups and the control (C vs CR and D vs DR respectively). The diastolic disfunction was detected in group D. The Glypican-1 and Syndecan-4 protein expression were significantly higher in group D when compared to the other groups and less expressed in group DR when compared to the other groups. Conclusion: The administration of RSV reversed both morphological changes and the global cardiac function, which showed very close values to the normal range values, without changing the hemodynamic and autonomic conditions

O crescimento gengival induzido por ciclosporina-A (CG) é caracterizado por uma variedade de sinalizações que envolvem fatores de crescimento e proteoglicanos, porém pouco compreendidas. Investigamos a expressão gênica dos proteoheparans sulfato de superfície celular sindecam-2 (SDC-2), -4 (SDC-4) e betaglicam nesse CG. A quantidade total e relativa de glicosaminoglicanos sulfatados (GAGs) e a distribuição de SDC-2 e SDC-4 no tecido gengival também foram analisadas. Métodos: A expressão de mRNA dos proteoglicanos SDC-2, SDC-4 e betaglicam foi analisada pela reação de polimerase em cadeia e transcrição reversa (RT-PCR) em amostras gengivais de 9 indivíduos com CG (grupo CsA) e 6 com gengiva normal (grupo controle). Os GAGs foram extraídos e purificados dos tecidos gengivais e analisados tanto por eletroforese em gel de agarose quanto por espectrofotometria. Foi realizada uma avaliação imunohistoquímica dos tecidos com anticorpos para SDC-2 e SDC-4, para sua localização nos tecidos. Os grupos foram comparados pelo teste t de Student. Resultados: Todos os proteoglicanos estudados mostraramse aumentados no grupo CsA (165% para SDC-2, 308% para SDC-4 e 42% para betaglicam), comparativamente ao grupo controle (P < 0.0001). Não foram observadas diferenças significativas na quantidade total e relativa de GAGs. A imunohistoquímica mostrou uma distribuição marcante de SDC-2 e SDC-4 no componentes epitelial, conjuntivo, vascular, nervoso e inflamatório, incluindo os compartimentos celulares e matriciais de toda a casuística. Nossos resultados revelam expressão aumentada de mRNA de SDC-2, SDC-4 e betaglicam no crescimento gengival induzido pela ciclosporina-A, porém não se observaram diferenças na quantidade de glicosaminoglicanos sulfatados em relação ao tecido gengival não exposto ao fármaco. / Cyclosporin-induced gingival overgrowth (CIGO) comprises a variety of signaling pathways including growth factors and proteoglycans that remains not fully understood. We investigated the gene expression of the cell-surface heparan sulfate proteoglycans syndecan-2 (SDC-2), -4 (SDC-4) and betaglycan in CIGO. Total and relative amounts of sulfated glycosaminoglycans (GAGs) and the distribution of SDC-2 and SDC-4 in the gingival tissue were also analyzed. Methods: mRNA expression of the proteoglycans SDC-2, -4 and betaglycan was analyzed by reverse transcription polymerase chain reaction (RT-PCR) in gingival samples obtained from 9 individuals with CIGO and 6 with a normal gingiva (control group). GAGs were extracted and purified from gingival tissues and analyzed by agarose gel electrophoresis and spectrophotometry. An immunohistochemical evaluation using panels of antibodies for SDC-2 and -4 was performed for localization in the tissues. Groups were compared by the Student's t test. Results: All proteoglycans expressions revealed increase in the CIGO group (165% for SDC-2, 308% for SDC-4 and 42% for betaglycan) compared to the control group (P < 0.0001). No significant differences were observed for the total and relative amounts of GAGs. Immunohistochemistry showed a marked distribution of SDC-2 and SDC-4 in gingival epithelial, connective, vascular, neural and inflammatory components comprising cellular and matrix environments in both groups. Our results reveal increased mRNA expression of SDC-2, SDC-4 and betaglycan in CIGO, but no significant differences in the sulfated glycosaminoglycans component in situ.