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A potencial função do nodal na endometrose da égua
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Resumo(s)
Alguns membros da superfamília do TGFβ, tais como o Nodal e o TGFβ1, têm um papel importante na reprodução da égua, sendo que a sua disfunção pode contribuir para patologias uterinas. A endometrose é uma doença degenerativa em que o endométrio normal vai sendo substituído por tecido fibrótico. O objectivo deste estudo consistiu em avaliar: (i) como o Nodal pode influenciar o nível de mRNA dos recetores da PGE2 (EP2; EP4), do TGFβ1 (ALK5; TGFRII), e os próprios (ALK4; ALK7), e ainda, a secreção de prostaglandinas (PGs; PGE2; PGF2α) no endométrio equino; e (ii) como a fase do ciclo éstrico e grau de endometrose pode influenciar estas vias. Endométrios da fase folicular (FF; n=6) e da fase lútea (FL; n=6) foram classificados de acordo com o sistema de Kenney e Doig em categorias I e IIA (n=7), ou IIB e III (n=5). Os explantes foram incubados (24h; 37ºC, 5% CO2) com TNFα, ocitocina ou Nodal (0.1;1;10 ng/mL). A expressão de mRNA foi avaliada por qRT-PCR e a medição de prostaglandinas por ELISA. Em endométrios de categoria I/IIA, o Nodal inibiu a expressão génica de EP2, EP4 e ALK4 e estimulou a de TGFRII, em ambas as fases do ciclo éstrico; e estimulou também os níveis de mRNA de ALK5 e ALK7, apenas na FL. Em endométrios de categoria IIB/III, o Nodal estimulou os níveis de mRNA de EP2, EP4 e ALK5, na FF, e de ALK4 e ALK7, na FL, embora tenha inibido TGFRII e ALK4, na FF, e EP2, EP4, ALK5 e TGFRII na FL. O Nodal na concentração testada mais baixa (0.1ng/mL) estimulou a produção de PGE2 na FF e FL, enquanto que numa concentração superior a inibiu na FF (1ng/mL). A produção de PGF2α foi estimulada na FL com Nodal (0.1 e 10ng/mL). Concluindo, o Nodal parece estar envolvido na endometrose da égua, por afetar negativamente a sinalização da PGE2 anti-fibrótica e positivamente a da citocina pró-fibrótica TGFβ1 e a produção de PGF2α.
ABSTRACT - THE POTENCIAL ROLE OF NODAL IN MAR ENDOMETROSIS - Members of TGFβ superfamily, as Nodal and TGFβ1, have an important role in mare´s reproduction, and as such, their dysfunction may contribute for uterine pathologies. Endometrosis is a degenerative process with a switch of normal endometrium to fibrotic tissue. The aim of the study was to assess: (i) how Nodal may influence the receptors of PGE2 (EP2; EP4), TGFβ1 (ALK5; TGFRII), and its own (ALK4; ALK7) mRNA level and prostaglandin (PG) secretion in equine endometrium; and (ii) estrous cycle and endometrosis influence on these vias. Endometria from follicular (FP; n=6) and mid luteal phases (MLP; n=6) were classified in Kenney and Doig´s categories (cat) I and IIA (n=7), or IIB and III (n=5). Endometrium explants were incubated (24h; 37ºC, 5% CO2) with TNF, oxytocin or Nodal (0.1, 1; 10ng/mL). The mRNA expression was assessed by qRT-PCR and ELISA was used for PG measurement. In cat I/IIA endometria, Nodal down-regulated EP2, EP4 and ALK4 mRNA expression and up-regulated TGFRII in both FP and MLP; and ALK5 and ALK7 only in MLP. In cat IIB/III, Nodal up-regulated mRNA levels of EP2, EP4 and ALK5 in FP, and ALK4 and ALK7 in MLP, whereas it inhibited TGFRII and ALK4 in FP, and EP2, EP4, ALK5 and TGFRII in MLP. Nodal (0.1ng/mL) stimulated PGE2 production in both FF and FL, while at a higher concentration (1ng/mL) it decreased PGE2 in FP. The production of PGF2α increased in MLP with Nodal stimulation (at 0.1 and 10ng/mL). In conclusion, Nodal may be involved in endometrosis in the mare, by impairment of anti-fibrotic PGE2 and pro-fibrotic TGFβ1 signaling pathways and increasing PGF2α production.
ABSTRACT - THE POTENCIAL ROLE OF NODAL IN MAR ENDOMETROSIS - Members of TGFβ superfamily, as Nodal and TGFβ1, have an important role in mare´s reproduction, and as such, their dysfunction may contribute for uterine pathologies. Endometrosis is a degenerative process with a switch of normal endometrium to fibrotic tissue. The aim of the study was to assess: (i) how Nodal may influence the receptors of PGE2 (EP2; EP4), TGFβ1 (ALK5; TGFRII), and its own (ALK4; ALK7) mRNA level and prostaglandin (PG) secretion in equine endometrium; and (ii) estrous cycle and endometrosis influence on these vias. Endometria from follicular (FP; n=6) and mid luteal phases (MLP; n=6) were classified in Kenney and Doig´s categories (cat) I and IIA (n=7), or IIB and III (n=5). Endometrium explants were incubated (24h; 37ºC, 5% CO2) with TNF, oxytocin or Nodal (0.1, 1; 10ng/mL). The mRNA expression was assessed by qRT-PCR and ELISA was used for PG measurement. In cat I/IIA endometria, Nodal down-regulated EP2, EP4 and ALK4 mRNA expression and up-regulated TGFRII in both FP and MLP; and ALK5 and ALK7 only in MLP. In cat IIB/III, Nodal up-regulated mRNA levels of EP2, EP4 and ALK5 in FP, and ALK4 and ALK7 in MLP, whereas it inhibited TGFRII and ALK4 in FP, and EP2, EP4, ALK5 and TGFRII in MLP. Nodal (0.1ng/mL) stimulated PGE2 production in both FF and FL, while at a higher concentration (1ng/mL) it decreased PGE2 in FP. The production of PGF2α increased in MLP with Nodal stimulation (at 0.1 and 10ng/mL). In conclusion, Nodal may be involved in endometrosis in the mare, by impairment of anti-fibrotic PGE2 and pro-fibrotic TGFβ1 signaling pathways and increasing PGF2α production.
Descrição
Dissertação de Mestrado Integrado em Medicina Veterinária
Palavras-chave
endométrio endometrose fibrose égua Nodal TGFβ1 PGE2 PGF2α EP2 EP4 ALK5 TGFRII ALK4 ALK7 expressão génica endometrium endometrosis fibrosis mare gene expression
Contexto Educativo
Citação
Morazzo, S.F. (2017). A potencial função do nodal na endometrose da égua. Dissertação de mestrado. Universidade de Lisboa, Faculdade de Medicina Veterinária, Lisboa.
Editora
Universidade de Lisboa, Faculdade de Medicina Veterinária