avAbanico veterinarioAbanico vet2007-428X2448-6132Sergio Martínez González10.21929/abavet2019.92400224Artículos de revisiónRevisión: Función y regresión del cuerpo lúteo durante el ciclo estral de la vaca0000-0001-9538-725XAréchiga-FloresCarlos1*0000-0001-9650-3312Cortés-VidauriZimri10000-0002-2080-508XHernández-BrianoPedro10000-0001-9255-5350Flores-FloresGilberto10000-0002-8676-7768Rochín-BerumenFabiola10000-0002-7159-6927Ruiz-FernándezEduardo1Unidad Académica de Medicina Veterinaria y Zootecnia, Universidad Autónoma de Zacatecas, Zacatecas, México. arechiga.uaz@gmail.com, mvzzcv@hotmail.com, phbriano@gmail.com, doktorflores@yahoo.com.mx, fabiolauaz@outlook.com, halcon58@hotmail.comUniversidad Autónoma de ZacatecasUnidad Académica de Medicina Veterinaria y ZootecniaUniversidad Autónoma de ZacatecasZacatecasMexicoarechiga.uaz@gmail.commvzzcv@hotmail.comphbriano@gmail.comdoktorflores@yahoo.com.mxfabiolauaz@outlook.comhalcon58@hotmail.com*Autor responsable y de correspondencia: Aréchiga-Flores Carlos. Unidad Académica de Medicina Veterinaria y Zootecnia de la Universidad Autónoma de Zacatecas; Jardín Juárez No. 147, Col. Centro, Zacatecas, Zacatecas, México, CP 98000.3007202120199e924060220192810201905112019Este es un artículo publicado en acceso abierto bajo una licencia Creative CommonsRESUMEN
El cuerpo lúteo (CL) es una estructura ovárica que produce progesterona para mantener la gestación, inicia su crecimiento a partir del tercer día de iniciado el estro creciendo hasta el décimo octavo día. Sí, el CL es fertilizado la formación del embrión producirá el interferón τ (IFN-τ) sustancia responsable del reconocimiento materno de la gestación (RMG) en los bovinos durante toda su gestación. Al no ser fertilizado el CL el endometrio uterino secreta prostaglandinas F2α (PGF2α) causando la lisis del cuerpo lúteo. Los niveles séricos de la progesterona disminuyen generando desbloqueo del hipotálamo y secreción de la hormona liberadora de gonadotropinas (GnRH) para activar el eje hipotalámico-hipofisiario-gonadal que desarrolla folículos nuevos de 48 a 72 h posteriores e inicia un nuevo estro. La presente revisión bibliográfica detalla los mecanismos fisiológicos involucrados en la formación del cuerpo lúteo durante el ciclo estral de los bovinos.
En las vacas el CL se desarrolla a partir de las células de la teca y de la granulosa, ambos componentes del folículo ovulatorio que alojan al ovocito. A partir de estas estructuras se forman células pequeñas y grandes para formar el CL que produce la hormona progesterona (P4), pero en hembras no gestantes sufre regresión al finalizar el ciclo estral (Niswender et al., 1985). (Cortés-Vidauri et al., 2018). La progesterona ejerce una retroalimentación negativa sobre el hipotálamo e hipófisis para reducir la secreción de las gonadotropinas (hormonas FSH y LH), e impedir se presenten ovulaciones subsecuentes (Stevenson y Britt, 1972; Ireland y Roche, 1982; Wiltbank et al., 2002); y no se descarta la posible participación de otros factores (Gosselin et al., 2000).
La regresión del cuerpo lúteo disminuye la secreción de progesterona a niveles previos a la formación del CL. La vaca presenta otro celo con ovulación y una nueva oportunidad para aparearse y concebir (Hansel et al., 1973; Juengel et al., 1993; Miyamoto et al., 2009). La prostaglandina F2α (PGF2α) producida en el endometrio uterino realiza la regresión del CL al disminuir el flujo sanguíneo hacia el ovario, disminuye la adenosin monofosfato cíclico (AMPc), conocida como el segundo mensajero y la acción esteroidogénica; causa una disminución en el número de receptores hormonales para la hormona luteinizante así como la presencia y acción del óxido nítrico. En la actualidad existe información relacionada con la regresión del CL generada por distintos grupos de investigadores, pero se encuentra dispersa. Por lo tanto, la presente revisión bibliográfica tiene como propósito analizar y discutir, en forma sucinta, la función del CL, así como la participación de la PGF2α en su regresión funcional y estructural.
CUERPO LÚTEO
El cuerpo lúteo (CL) es una glándula transitoria productora de progesterona, en la vaca se forma a partir de las células formadoras del folículo ovulatorio (la teca y granulosa). Esta hormona regula la duración del ciclo estral y suprime la ovulación, con lo cual se reduce la función cíclica (Rodgers et al., 1988). Pero en las hembras preñadas mantiene la gestación, proporcionando al embrión las condiciones uterinas adecuadas para su desarrollo y el de la glándula mamaria (Niswender et al., 2000).
El CL se compone de células parénquimales esteroidogénicas, secretoras de progesterona y células no parenquimales; células vasculares endoteliales, fibroblastos linfocitos y macrófagos (O’Shea et al., 1989; Lei et al., 1991; Reynolds y Redmer, 1999). La mayoría de las células esteroidogénicas se localizan adyacentes a los capilares (Zheng et al., 1993). La angiogénesis se compone de vasculatura sanguínea condensada y se desarrolla bajo la influencia de factores angiogénicos, estimulados por el factor vascular de crecimiento endotelial A y el factor de crecimiento fibroblástico básico, entre otros (Connolly, 1991; Ferrara y Davis-Smyth, 1997; Reynolds y Redmer, 1999; Berisha y Schams, 2005). Estos factores y sus receptores presentan elevada expresión génica durante el desarrollo del CL, pero se reduce en la parte media de la fase lútea (Berisha et al., 2000; 2008). En el CL existen 2 tipos celulares: 1) células lúteas grandes (CLG), originadas a partir de las células de la granulosa del folículo ovárico), y 2) células lúteas pequeñas (CLP), originadas a partir de las células de la teca interna del folículo ovárico que ovula después del estro y forma una estructura de transición llamada cuerpo hemorrágico (CH). Posteriormente se forma el cuerpo lúteo con ambos tipos celulares, que sintetizan progesterona (P4); hormona responsable de la gestación.
Las CLG poseen receptores para la hormona FSH y las CLP; poseen receptores para la hormona LH. Por lo tanto, la hormona progesterona (P4) se sintetiza por la influencia de la hormona luteinizante (LH); pero la progesterona se estimula también por su propia secreción de bio-reguladores autócrinos y parácrinos (Skarzynski y Okuda, 1999; Duras et al., 2005). Además, estimula la producción de prostaglandinas (F2α y E2) y oxitocina al inicio del ciclo, pero inhibe la secreción de prostaglandina F2α en la parte media (Sarzynski y Okuda, 1999; Okuda et al., 2004). Por lo tanto, la progesterona intraluteal promueve la supervivencia del CL mediante la estimulación de su propia secreción (Juengel et al., 1993; Rueda et al., 1997a,b; Okuda et al., 2004).
El CL en la vaca, produce factores vasoactivos para regular el flujo sanguíneo, como es la producción de progesterona, óxido nítico (ON) (Skarzynski et al., 2000a, b; Zerani et al., 2007; Kowalczyk-Zieba et al., 2014), endotelina-1 (Girsh et al., 1995; 1996a, b; Miyamoto et al., 1997), angiotensina-II (Hayashi et al., 2000) y prostaglandina F2α (Shemesh y Hansel, 1975a, b; Miyamoto et al., 1993). Pero en el ganado bovino la secreción de progesterona incrementa conforme se presenta la angiogénesis y la proliferación de las células lúteas durante los primeros 6 días después de la ovulación. El incremento puede ir de 1 ng/ml tres días después de la ovulación, a 3 ng/ml a los 6 días postovulación; alcanzando la mayor concentración sanguínea de los 10 a los 14 días. Posteriormente hay reducción de progesterona después del día 16, hasta registrar el nivel que tenía al principio del ciclo causado por la prostaglandina F2α, hormona encargada de su regresión (Skarzynski et al., 2003a; b).
SÍNTESIS DE LA PROGESTERONA
La progesterona (P4) es sintetiza a partir del colesterol, la célula lútea los obtiene de la circulación sanguínea unido a lipoproteínas de baja (LDLP) y alta densidad (HDLP) (Grumer y Carroll, 1988; Carroll et al., 1992). Si es necesario la célula lútea sintetiza colesterol a partir del acetato que se almacena dentro de la célula como ester de colesterol, por la acción de la acil CoA colesterol acil transferasa. La enzima colesterol esterasa neutra transforma el ester de colesterol en colesterol cuando se requiere (Grumer y Carroll, 1988).
Para iniciar la síntesis de esteroides, el colesterol debe penetrar en la mitocondria y transformarse en pregnenolona. En respuesta a un estímulo esteroidogénico, la proteína reguladora aguda de los esteroides (STAR) transporta el colesterol al interior de la mitocondria y la enzima fragmentadora de la cadena lateral del citocromo P450, lo transforma en pregnenolona (Stocco y Ascoli, 1993; Stocco, 1997; 2001). Finalmente, en el retículo endoplásmico liso la pregnenolona se transforma en progesterona bajo, la acción de la enzima 3 β-hidroxi esteroide dehidrogenasa (Holt, 1989; Rabiee et al., 1999; Niswender, 2002).
La progesterona puede promover su propia secreción en la célula lútea o actuar sobre su órgano blanco (Niswender y Nett, 1994; Niswender et al., 1994). La LH incrementa simultáneamente la expresión de los genes codificadores para la síntesis de la proteína StAR y las enzimas fragmentadoras de la cadena lateral P450 y 3β-hidroxi-esteroide deshidrogenasa (Kotwica et al., 2004; Rekawiecki et al., 2005). Otros factores que promueven la síntesis de progesterona a través de enzimas que participan en la síntesis de progesterona, son la propia progesterona, noradrenalina y la prostaglandina E2 (PGE2) (Kotwica et al., 2002; 2004; Rekawiecki et al., 2005; Freitas de Melo y Ungerfeld, 2016; Berisha et al., 2018). La progesterona a su vez, estimula también la secreción lútea de PGE2 (Kotwica et al., 2004) y la noradrenalina la síntesis de oxitocina (Bogacki y Kotwica, 1999).
La P4 ejerce una retroalimentación negativa sobre la síntesis de GnRH producido por las neuronas hipotalámicas; por lo anterior, GnRH, FSH y LH son suprimidas. La P4 reduce la cantidad de receptores de GnRH para la hipófisis anterior (adenohipófisis). Por otro lado, la P4 ejerce una influencia positiva sobre el endometrio uterino y favorece la secreción de materiales hacia el lumen uterino; aunque también inhibe al miometrio, reduce las contracciones y la tonicidad; Incluso la P4 promueve el desarrollo alveolar en la glándula mamaria durante la gestación.
REGRESIÓN DEL CL
Durante la regresión del CL, es muy importante que el ovario mantenga su mismo tamaño y desaparezcan las células lúteas. La prostaglandina F2α endógena promueve la regresión del cuerpo lúteo (luteólisis) al final del ciclo estral (Niswender et al., 1976; McCracken et al., 1981; Lindell et al., 1982; Acosta et al., 2002). El proceso inicia del día 17 al 19 del ciclo (McCracken et al., 1999). La secreción de progesterona se reduce hasta niveles basales, desaparece la retroalimentación negativa sobre el eje hipotálamo- hipófisis; en consecuencia inicia otro ciclo estral, la vaca presenta una nueva oportunidad para concebir.
La prostaglandina F2α se produce en el endometrio uterino, debido a la interacción estradiol-oxitocina (Hansel et al., 1975; Ham et al., 1975; Hansel y Blair, 1996; Burns et al., 1997). El estradiol aumenta la secreción de prostaglandina F2α y estimula la síntesis de receptores para la oxitocina en el endometrio; la oxitocina actúa sobre el endometrio uterino, estimulando la secreción de prostaglandina F2α en forma pulsátil. La prostaglandina F2α de origen uterino estimula la secreción de la F2α en las células lúteas, en un proceso de auto-amplificación para completar la luteólisis (Kumagai et al., 2014).
La acción de la prostaglandina F2α sobre el cuerpo lúteo es tanto funcional como estructural; en ambas participan las especies reactivas de oxígeno (ROS), que incluyen al óxido nítrico (NO), superóxido y el hiperóxido anión del metabolismo del O2 (Juengel et al., 1993; Pate, 1994; Rueda et al., 1997a, b; Meidan et al., 1999). Las especies reactivas son compuestos con una molécula de oxígeno, portando un electrón sin aparear (Aruoma, 1999; Aruoma et al., 1999; Young and Woodside, 2001). Entidades químicas inestables, reactivas y vida efímera, con capacidad para combinarse con la mayoría de las moléculas que forman parte de la estructura celular; carbohidratos, lípidos, proteínas y ácidos nucleicos (Attaran et al., 2000; Szczpanska et al., 2003; Van Langendonckt et al., 2002).
La PGF estimula la síntesis de ON en las células endoteliales del CL, estimulando la producción intraluteal de PGF (Acosta et al., 2009; Lee et al., 2009; Lao et al., 2009; Lee et al, 2009; Skarzynski et al., 2003a; b; Lee et al., 2010). La PGF2α se une a sus receptores en la membrana plasmática de las células lúteas, la formación del complejo PGF2α y receptor; abren los canales de Ca++, permitiendo su entrada al espacio intracelular, iniciando los procesos de apoptosis en células lúteas. El CL es un órgano vascularizado con células endoteliales abundantes que producen óxido nítrico (ON), inhibiendo la síntesis y secreción de progesterona (Lei et al., 1991; Lao et al., 2009; Lee et al., 2009) (Korzekwa et al., 2004, 2006; 2007; 2014; Skarzynski y Okuda, 2000); así como la apoptosis de las células lúteas (Korzekwa et al., 2006; 2014).
La unión del complejo prostaglandina F2α- receptor estimula la síntesis de la protein- cinasa tipo C (PK-C), que inhibe de manera suimultánea la síntesis de P4. Funcionalmente el cuerpo lúteo reduce la secreción de progesterona, en su estructura se genera la degradación del tejido lúteo, apoptosis y necrosis; hasta que disminuye su volumen y desaparece (Niswender et al., 1976; McCracken et al., 1999; Acosta et al., 2002; Stocco et al., 2007). La luteólisis funcional se realiza 12 h después de la inyección de PGF2α, y 12 h posteriores se lleva a cabo la luteolisis estructural (Neuvias et al., 2004a;b; Mishra et al., 2018).
REGRESIÓN FUNCIONAL DEL CL
El ON impide la síntesis y secreción de progesterona por medio de la inhibición de la expresión de la proteína StAR, así como las enzimas fragmentadoras de la cadena lateral citocromo P450scc y 3-βHSD (Sessa et al., 1994; Sawada y Carlson, 1996; Skarzynski y Okuda, 2000; Korzekwa et al., 2004, 2006; 2007; 2014; Girsh et al., 1995; 1996a,b; Skarzynski et al., 2003a;b; Rekawiecki et al., 2005). En consecuencia, el colesterol no puede ingresar a la mitocondria y el colesterol disponible dentro de ella no se transformará en pregnenolona, y no se convertirá en progesterona. El nivel de la progesterona disminuye a una concentración basal y se retirará la retroalimentación negativa sobre el eje hipotálamo-hipófisis, se presentaré otro celo y una nueva oportunidad para empadrarse y concebir.
REGRESIÓN ESTRUCTURAL DEL CL
La regresión estructural del CL se realiza por apoptosis y necrosis fisiológica de las células lúteas esteroidogénicas (Juengel et al., 1993; Rueda et al., 1995, 1997a;b; Tilly, 1996; Korzekwa et al., 2006; Park et al., 2017).
Apoptosis
Apoptosis es la muerte celular programada en un modelo fisiológico, donde la célula diseña y ejecuta su propia muerte. Se efectúa a través de colapso celular codificado genéticamente con encogimiento celular; desintegración de proteínas, condensación de la cromatina y degradación del ADN; además de la fragmentación celular y formación de cuerpos apoptóticos. Finalmente, las células vecinas como los fibroblastos o células epiteliales, fagocitan los cuerpos apoptóticos sin desencadenar una reacción inflamatoria (Compton, 1992).
La apoptosis se realiza por medio de las caspasas (Clarke, 1990; Clark y Lampert 1990; Tilly, 1996; Carambula et al., 2002); las cuales se han considerado como sus ejecutoras que participan como iniciadoras y ejecutoras del proceso (Cohen, 1997). La lutéolisis se lleva a cabo en las células lúteas esteroidogénicas (SLC) y en las células lúteas endoteliales (LEC) (Juengel et al., 1993; Rueda et al., 1995; 1997a,b). Su actividad la llevan a cabo principalmente a través de una vía extrínseca, por un dominio de muerte o receptor, y por vía intrínseca de tipo mitocondrial.
Vía Extrínseca
La vía extrínseca se ejecuta por gran variedad de factores involucrados en la apoptosis (Friedman et al., 2000; Petroff et al., 2001; Taniguchi et al., 2002; Okuda et al., 2004; Korzekwa et al., 2006; Hojo et al., 2010; 2016) como el factor de necrosis tumoral α (TNF), interferón-γ (IFNG), ligando de FAS (FASL) y óxido nítrico (NO) (Friedman et al., 2000; Petroff et al., 2001; Nakamura y Sakamoto, 2001; Taniguchi et al., 2002; Korzekwa et al., 2006; Hojo et al., 2010; 2016). Estos factores también se han encontrado que participan en la regresión vascular del CL; por ejemplo, el receptor TNF tipo 1(TNFR1); así como la proteína relacionada llamada Fas (CD95) y su ligando (Fas ligando); disponen de dominios de muerte intracelulares que reclutan proteínas adaptadoras como el dominio de muerte asociado al receptor TNF (TRADD) y al dominio de muerte asociado a Fas (FADD); además, a cisteína-proteasas como las caspasas. La unión del ligando de muerte con su receptor correspondiente conlleva a la formación de un sitio de unión para la proteína adaptadora, como consecuencia se forma un complejo ligando-receptor- adaptador conocido como DISC (complejo de señalización que induce la muerte). Este ensambla y activa la pro-caspasa 8, con la subsiguiente constitución de caspasa-8, forma activa de la enzima que constituirá la caspasa iniciadora y estableciendo la cascada de caspasas. En el CL de la vaca se localiza el TNF (Sakumoto et al., 2011), e induce el interferón-γ y Fas en el proceso de apoptosis, mediante el incremento de la activación de caspasa-3 (Taniguchi et al., 2002); que es finalmente la molécula efectora (Nagata, 1997; Muzio et al., 1998).
Vía Extrínseca
La vía intrínseca se inicia dentro de la célula por medio de estímulos internos como hipoxia; durante la apoptosis a nivel mitocondria se activa la caspasa, lo que estimula la unión de caspasa pro-apoptosis con la mitocondria, e inhibe la asociación de anti- apoptosis Bcl-2. Esto conduce a la filtración de citocromo-c de la mitocondria hacia el citosol, el cual promueve la formación de apoptosoma y desencadena la activación del efector Caspasa (Scaffidi et al., 1998). En la familia Bcl se encuentran dos grupos; proteínas pro-apoptóticas, como Bax y anti-apoptóticas, como Bcl-2. Su función como se anotó, se relaciona con la liberación de citocromo-c, para la formación de apoptosoma, y activar la caspasa. Las pro- y las anti-apoptóticas liberan y frenan la liberación de citocromo-c de la mitocondria hacia el citoplasma, respectivamente. Con base en lo anterior, la activación de la ruta mortal involucra la liberación de citocromo-c dentro del citosol, que a su vez promueve la formación del apoptosoma y activación del efector caspasa-3, con la subsiguiente fragmentación del ADN (Thorneberry y Lazebnik, 1998), en el paso final de la apoptosis (Scaffidi et al., 1998).
La participación de ON se realiza a través de la estimulación de la expresión propoptotica de Bax, sin efecto en la expresión de ARNm de Fas y Bcl-2 (Korzekwa et al., 2006). En consecuencia, disminuye la proporción de Bcl-2 a bax, proporción ARNm Bcl-2 y ARNm Bax en el CL del bovino, disminuye en la luteólisis; además, en estas células in vitro el ON estimula la expresión y la actividad de la caspasa-3 (Skarzynski et al., 2005; Korzekwa et al., 2006). También el ON incrementa la producción de PGF2α intraluteal y reduce la expresión de ARNm superóxido dismutasa (SOD) y su proteína en cultivo de 24 horas de LECs bovinas (Lee et al., 2010). El incremento de la PGF intraluteal constituye un sistema de amplificación, donde un pequeño estímulo desencadena una serie de reacciones que aumentan la respuesta celular; de esta manera aumenta su función, y la reducción de SOD para incrementar el súper óxido intraluteal. La reducción de SOD a las 24 h podría incrementar la acumulación intraluteal de SO para la promoción de la luteólisis estructural (Nakamura y Sakumoto, 2001; Buttke y Sandstrom, 1994; Rothstein et al., 1994; Suhara et al., 1998). El SOD cataliza la dismutación de superóxido a H2O2 y oxígeno, y como consecuencia mantiene bajo el nivel de superóxido (Fridovich, 1995).
Necroptosis
La apoptosis se puede realizar por un mecanismo independiente a las caspasas, como una ruta alterna para la muerte celular o necroptosis y se lleva a cabo por los receptores que interactúan con la proteína quinasa (RIPK) como el 1 (RIPK1) y 3 (RIPK3) (Festjens et al., 2007; Hitomi et al., 2008; Degterev et al., 2008; Degterev et al., 2008; Declercq et al., 2009; Cho et al., 2009; He et al., 2009; Zhang et al., 2009; Christofferson y Yuan, 2010; Vandenabeele et al., 2010). El RIPK1 se une a la membrana de TNFR1 y FAS; receptores del ligando inductores de apoptosis TNF1 (TRAILR1) y 2 (TRAILR2), para desencadenar la ruta necroptótica de los miembros de la súper familia de receptores TNF (Holler et al., 2000). El RIPK3 es un modulador necesario para la necroptosis, pero particularmente el TNFR1 y FAS. (Taniguchi et al., 2002; Cho et al., 2009; He et al., 2009; Zhang et al., 2009; Vanlangerakker et al., 2012). (Zhang et al., 2009; Vanlangerakker et al., 2012; Moujalled et al., 2013). Las RIPKs dependientes de necroptosis participan en la luteólisis estructural bovina (Christofferson y Yuan, 2010; Vandenabeele et al., 2010).
IRRIGACIÓN SANGUÍNEA
La prostaglandina F2α participa en la vasodilatación y en la vasoconstricción del CL (Wiltbank et al., 1995; Díaz et al., 2002); en la luteólisis espontánea y aplicación de prostaglandina F2α exógena continúa un incremento del flujo sanguíneo en la periferia del cuerpo lúteo (Acosta et al., 2002; Miyamoto et al., 2005; Ginther et al., 2007; Miyamoto y Shirasuna, 2009; Shirasuna et al., 2012). Esto se debe al ON que tiene capacidad vasodilatadora e inhibe directamente la secreción de la progesterona, induciendo la apoptosis de las células lúteas (Skarzynski et al., 2003a, b; Shirasuna et al., 2008a, b,c; Shirasuna et al., 2012). El efecto de la prostaglandina sobre la secreción de ON y el incremento agudo del flujo sanguíneo en la periferia del cuerpo lúteo se ha considerado el primer indicador fisiológico de la luteólisis (Shirasuna et al., 2008a,b,c; 2010; 2012). La influencia de la prostaglandina F2α sobre el óxido nítrico se ha comprobado mediante su efecto sobre productos intermedios.
La aplicación de prostaglandina F2α estimula la expresión endotelial del óxido nítrico sintasa (enzima encargada de transformar la L-arginina en óxido nítrico) en el cuerpo lúteo, 30 minutos después de su aplicación, con el correspondiente incremento de flujo sanguíneo luteal (Shirasuma et al., 2008a,b,c). Por otro lado, el efecto del óxido nítrico sobre el flujo sanguíneo se ha demostrado por medio de su promoción e inhibición. El abastecedor de óxido nítrico (S-nitroso-N-acetyl-D,L-pellicilamine) en el cuerpo lúteo, induce incremento agudo del flujo sanguíneo y acorta el ciclo estral. Además, la inyección del inhibidor de óxido nítrico sintasa (L-NG-nitroarginine methyl ester) dentro del cuerpo lúteo suprime completamente el incremento agudo del flujo sanguíneo provocado por la prostaglandina F2α, y retarda el inicio de la luteólisis (Shirasuma et al., 2008b).
La prostaglandina F2α, después de su efecto vasodilatador, limita el suministro de oxígeno y nutrientes al cuerpo lúteo para culminar la luteólisis por medio de inhibición de angiogénesis, angiolisis y vasoconstricción (Guilbault et al., 1984; Acosta et al., 2002). Treinta minutos posteriores a la inyección de prostaglandina F2α en la parte media del ciclo; se ha observado regulación a la baja de la expresión del ARNm del factor vascular de crecimiento endotelial y del factor de crecimiento trofoblástico básico; así como la expresión proteica del factor vascular de crecimiento endotelial A (Berisha et al., 2008; Shirasuna et al., 2010). Con esto la prostaglandina F2α inhibe el desarrollo de los vasos sanguíneos delgados y posteriormente los gruesos (Hojo et al., 2009).
La prostaglandina F2α estimula la biosíntesis de endotelina-1 (EDN1) y la expresión de su ARNm; así como angiotensina II (Ang II) y la expresión de la enzima convertidora- angiotensina, tanto in vivo como in vitro (Girsh et al., 1996b; Miyamoto et al., 1997; Hayashi y Miyamoto, 1999). Estos son potentes vasoconstrictores que operan en respuesta a la prostaglandina F2α para reducir el suministro sanguíneo, y por consiguiente disminuir la disponibilidad de oxígeno y nutrientes al cuerpo lúteo durante la luteólisis (Girsh et al., 1996a; Miyamoto et al., 1997; Hayashi y Miyamoto, 1999). EDN1 y Ang II también se han encontrado que inhiben la secreción de progesterona en el cuerpo lúteo in vitro (Stirling et al., 1990; Girsh et al., 1996a; Miyamoto et al., 1997), lo cual los ubica como factores que participan en la luteólisis funcional.
Las concentraciones circulantes de progesterona están determinadas por un balance entre la producción primaria de P4, por parte del CL; y el metabolismo de la P4, por parte del hígado. El volumen del tejido lúteo, el número y funcionalidad de las células lúteas grandes son los principales factores que determinan la producción de la hormona progesterona (Gregson et al., 2016). La tasa metabólica de la P4 generalmente está determinada por el flujo sanguíneo hepático y puede ser muy importante, especialmente en vacas lecheras, para determinar las concentraciones circulantes de progesterona (P4).
Al realizar la inseminación artificial a tiempo fijo (IATF), se ha logrado incrementar las concentraciones de P4, al incrementar el número de CL´s, inducir la aparición de un CL accesorio, ó al suplementar fuentes exógenas de la hormona P4. Controlar la dieta también puede modificar las concentraciones de P4; sin embargo aún no se cuenta con estrategias prácticas que permitan alterar a la P4 en la dieta a nivel de campo y de manera práctica. Al elevar la P4 antes de la inseminación artificial a tiempo fijo (IATF), generalmente se reducen las ovulaciones dobles y se incrementa la fertilidad de la inseminación a tiempo fijo. Al elevar la P4 al momento de la IA, genera incrementos ligeros de la P4 circulante, posiblemente debido a una regresión lútea inadecuada que pudiera comprometer la fertilidad en respuesta a la IA. Al elevar la P4 después de la IA, los niveles circulantes de P4 son críticos para el crecimiento embrionario y el establecimiento y mantenimiento de la gestación. Varios estudios han intentado incrementar la fertilidad aumentando los niveles circulantes de P4 después de la IATF. Existe un meta-análisis que indica un ligero incremento de la fertilidad (3 a 3.5%), principalmente en vacas de primer parto (Wiltbank et al., 2014). La investigación a futuro deberá centrarse en manipular la P4 en la vaca para garantizar un mayor éxito en la función reproductiva.
CONCLUSIÓN
El cuerpo lúteo ovárico es una glándula de vida efímera que produce la hormona progesterona. La progesterona ejerce retroalimentación negativa sobre el hipotálamo e hipófisis para reducir la secreción de gonadotropinas para evitar ovulaciones. En las vacas que no conciben la PGF2α, realiza su regresión con lo que se reduce la secreción de progesterona a niveles que se registraban antes de su formación. La regresión del cuerpo lúteo es funcional y estructural. En la regresión funcional se impide la síntesis y secreción de progesterona, pero la regresión estructural se realiza por medio de apoptosis y necroptosis de las células lúteas esteroidogénicas. La PGF2α participa en la irrigación del cuerpo lúteo aportando nutrientes.
Por lo tanto, en futuras investigaciones se debe concentrar la manipulación de prostaglandinas circulantes para garantizar un mayor éxito reproductivo, principalmente cuando se aplican programas de inseminación a tiempo fijo o predeterminado en hembras bovinas.
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The corpus luteum (CL) is an ovarian structure that produces progesterone to maintain pregnancy, begins its growth from the third day of the beginning of estrus growing until the eighteenth day. If the CL is fertilized, the formation of the embryo will produce the interferon τ (IFN-τ) substance responsible for maternal recognition of pregnancy (RMG) in cattle during their entire pregnancy. When CL is not fertilized, the uterine endometrium secretes prostaglandins F2α (PGF2α) causing lysis of the corpus luteum. The serum levels of progesterone decrease generating hypothalamus unlocking and gonadotropin-releasing hormone (GnRH) secretion to activate the hypothalamic-pituitary-gonadal axis that develops new follicles 48 to 72 h later and initiates a new estrus. This bibliographic review details the physiological mechanisms involved in the formation of the corpus luteum during the estrous cycle of cattle in the function and regression of the corpus luteum during the estrous cycle of cows.
In cows, CL develops from teak and granulosa cells, both components of the ovulatory follicle that house the oocyte. From these structures small and large cells are formed to form the CL that produces the hormone progesterone (P4), but in non-pregnant females it undergoes regression at the end of the estrous cycle (Niswender et al., 1985). (Cortés- Vidauri et al., 2018). Progesterone exerts a negative feedback on the hypothalamus and pituitary gland to reduce the secretion of gonadotropins (hormones FSH and LH), and prevent subsequent ovulations (Stevenson and Britt, 1972; Ireland and Roche, 1982; Wiltbank et al., 2002); and the possible participation of other factors is not ruled out (Gosselin et al., 2000).
Regression of the corpus luteum decreases progesterone secretion to levels prior to the formation of CL. The cow presents another zeal with ovulation and a new opportunity to mate and conceive (Hansel et al., 1973; Juengel et al., 1993; Miyamoto et al., 2009). The prostaglandin F2α (PGF2α) produced in the uterine endometrium performs the regression of the CL by decreasing the blood flow to the ovary, decreases the cyclic adenosine monophosphate (cAMP), known as the second messenger and the steroidogenic action; It causes a decrease in the number of hormonal receptors for luteinizing hormone as well as the presence and action of nitric oxide. Currently there is information related to the regression of the CL generated by different groups of researchers, but it is dispersed. Therefore, the present literature review aims to analyze and discuss, succinctly, the role of CL, as well as the participation of PGF2α in its functional and structural regression.
CORPUS LUTEUM
The corpus luteum (CL) is a transient progesterone-producing gland, in the cow it is formed from the ovulatory follicle-forming cells (teak and granulose). This hormone regulates the duration of the estrous cycle and suppresses ovulation, thereby reducing cyclic function (Rodgers et al., 1988). But in pregnant females it maintains pregnancy, providing the embryo with the uterine conditions suitable for its development and that of the mammary gland (Niswender et al., 2000).
The CL is composed of steroidogenic parenchymal cells secreting progesterone and non- parenchymal cells; endothelial vascular cells, lymphocyte and macrophage fibroblasts (O'Shea et al., 1989; Lei et al., 1991; Reynolds and Redmer, 1999). The majority of steroidogenic cells are located adjacent to the capillaries (Zheng et al., 1993). Angiogenesis is composed of condensed blood vasculature and develops under the influence of angiogenic factors, stimulated by vascular endothelial growth factor A and basic fibroblastic growth factor, among others (Connolly, 1991; Ferrara and Davis-Smyth, 1997; Reynolds and Redmer, 1999; Berisha and Schams, 2005). These factors and their receptors have high gene expression during the development of CL, but it is reduced in the middle part of the luteal phase (Berisha et al., 2000; 2008). In the CL there are 2 cell types: 1) large luteal cells (CLG), originating from granular cells of the ovarian follicle), and 2) small luteal cells (CLP), originating from teak cells Internal ovarian follicle that ovulates after estrus and forms a transitional structure called the hemorrhagic body (CH). The corpus luteum is subsequently formed with both cell types, which synthesize progesterone (P4); hormone responsible for pregnancy.
CLGs have receptors for the FSH hormone and CLP; they have receptors for the hormone LH. Therefore, the hormone progesterone (P4) is synthesized by the influence of luteinizing hormone (LH); but progesterone is also stimulated by its own secretion of autocratic and paracrine bio-regulators (Skarzynski and Okuda, 1999; Duras et al., 2005). In addition, it stimulates the production of prostaglandins (F2α and E2) and oxytocin at the beginning of the cycle, but inhibits the secretion of prostaglandin F2α in the middle part (Sarzynski and Okuda, 1999; Okuda et al., 2004). Therefore, intraluteal progesterone promotes CL survival by stimulating its own secretion (Juengel et al., 1993; Rueda et al., 1997a, b; Okuda et al., 2004).
CL in the cow produces vasoactive factors to regulate blood flow, such as the production of progesterone, nitric oxide (ON) (Skarzynski et al., 2000a, b; Zerani et al., 2007; Kowalczyk-Zieba et al., 2014), endothelin-1 (Girsh et al., 1995; 1996a, b; Miyamoto et al., 1997), angiotensin-II (Hayashi et al., 2000) and prostaglandin F2α (Shemesh and Hansel, 1975a, b; Miyamoto et al., 1993). But in cattle, progesterone secretion increases as angiogenesis and luteal cell proliferation occur during the first 6 days after ovulation. The increase can range from 1 ng/ml three days after ovulation, to 3 ng/ml at 6 days post- ovulation; reaching the highest blood concentration from 10 to 14 days. Subsequently, there is a reduction in progesterone after day 16, until the level it had at the beginning of the cycle caused by prostaglandin F2α, the hormone responsible for its regression (Skarzynski et al., 2003a; b).
SYNTHESIS OF PROGESTERONE
Progesterone (P4) is synthesized from cholesterol, the luteal cell obtains them from the blood circulation linked to low-density lipoproteins (LDLP) and high density (HDLP) (Grumer and Carroll, 1988; Carroll et al., 1992). If necessary, the luteal cell synthesizes cholesterol from the acetate that is stored inside the cell as a cholesterol ester, by the action of the acyl CoA cholesterol acyl transferase. The neutral cholesterol esterase enzyme transforms the cholesterol ester into cholesterol when required (Grumer and Carroll, 1988).
To start steroid synthesis, cholesterol must penetrate the mitochondria and transform into pregnenolone. In response to a steroidogenic stimulus, the acute steroid regulatory protein (STAR) transports cholesterol into the mitochondria and the fragmenting enzyme of the cytochrome P450 side chain transforms it into pregnenolone (Stocco and Ascoli, 1993; Stocco, 1997; 2001). Finally, in the smooth endoplasmic reticulum, pregnenolone is transformed into low progesterone, the action of the enzyme 3β-hydroxy steroid dehydrogenase (Holt, 1989; Rabiee et al., 1999; Niswender, 2002).
Progesterone can promote its own secretion in the luteal cell or act on its white organ (Niswender and Nett, 1994; Niswender et al., 1994). LH simultaneously increases the expression of the coding genes for the synthesis of the StAR protein and the fragmenting enzymes of the P450 and 3β-hydroxy-steroid dehydrogenase side chain (Kotwica et al., 2004; Rekawiecki et al., 2005). Other factors that promote the synthesis of progesterone through enzymes that participate in the synthesis of progesterone, are progesterone itself, norepinephrine and prostaglandin E2 (PGE2) (Kotwica et al., 2002; 2004; Rekawiecki et al., 2005; Freitas de Melo and Ungerfeld, 2016; Berisha et al., 2018). Progesterone, in turn, also stimulates the luteal secretion of PGE2 (Kotwica et al., 2004) and norepinephrine synthesis of oxytocin (Bogacki and Kotwica, 1999).
P4 exerts a negative feedback on the synthesis of GnRH produced by hypothalamic neurons; Therefore, GnRH, FSH and LH are suppressed. P4 reduces the amount of GnRH receptors for the anterior pituitary gland (adenohypophysis). On the other hand, P4 exerts a positive influence on the uterine endometrium and favors the secretion of materials into the uterine lumen; although it also inhibits the myometrium, it reduces contractions and tonicity; Even P4 promotes alveolar development in the mammary gland during pregnancy.
CL REGRESSION
During the regression of the CL, it is very important that the ovary remains the same size and the luteal cells disappear. Endogenous prostaglandin F2α promotes the corpus luteum regression (luteolysis) at the end of the estrous cycle (Niswender et al., 1976; McCracken et al., 1981; Lindell et al., 1982; Acosta et al., 2002). The process starts from day 17 to 19 of the cycle (McCracken et al., 1999). Progesterone secretion is reduced to baseline levels, negative feedback on the hypothalamus-pituitary axis disappears; consequently begins another estrous cycle, the cow presents a new opportunity to conceive.
Prostaglandin F2α is produced in the uterine endometrium, due to the estradiol-oxytocin interaction (Hansel et al., 1975; Ham et al., 1975; Hansel and Blair, 1996; Burns et al., 1997). Estradiol increases the secretion of prostaglandin F2α and stimulates the synthesis of receptors for oxytocin in the endometrium; Oxytocin acts on the uterine endometrium, stimulating the secretion of prostaglandin F2α in pulsatile form. Prostaglandin F2α of uterine origin stimulates the secretion of F2α in luteal cells, in a process of self- amplification to complete luteolysis (Kumagai et al., 2014).
The action of prostaglandin F2α on the corpus luteum is both functional and structural; both reactive oxygen species (ROS), which include nitric oxide (NO), superoxide and the anion hyperioxide of O2 metabolism, participate (Juengel et al., 1993; Pate, 1994; Rueda et al., 1997a, b; Meidan et al., 1999). Reactive species are compounds with an oxygen molecule, carrying an unpaired electron (Aruoma, 1999; Aruoma et al., 1999; Young and Woodside, 2001). Unstable chemical entities, reactive and ephemeral life, with the ability to combine with most of the molecules that are part of the cellular structure; carbohydrates, lipids, proteins and nucleic acids (Attaran et al., 2000; Szczpanska et al., 2003; Van Langendonckt et al., 2002).
PGF stimulates ON synthesis in CL endothelial cells, stimulating intraluteal production of PGF (Acosta et al., 2009; Lee et al., 2009; Lao et al., 2009; Lee et al, 2009; Skarzynski et al., 2003a; b; Lee et al., 2010). PGF2α binds to its receptors in the plasma membrane of luteal cells, the formation of the PGF2α and receptor complex; they open the Ca ++ channels, allowing their entry into the intracellular space, initiating the processes of apoptosis in luteal cells. CL is a vascularized organ with abundant endothelial cells that produce nitric oxide (ON), inhibiting the synthesis and secretion of progesterone (Lei et al., 1991; Lao et al., 2009; Lee et al., 2009) (Korzekwa et al., 2004, 2006; 2007; 2014; Skarzynski and Okuda, 2000); as well as the apoptosis of the luteal cells (Korzekwa et al., 2006; 2014).
The binding of the prostaglandin F2α-receptor complex stimulates the synthesis of protein kinase type C (PK-C), which simultaneously inhibits the synthesis of P4. Functionally the corpus luteum reduces the secretion of progesterone, in its structure the degradation of the luteal tissue, apoptosis and necrosis is generated; until its volume decreases and disappears (Niswender et al., 1976; McCracken et al., 1999; Acosta et al., 2002; Stocco et al., 2007). Functional luteolysis is performed 12 h after the injection of PGF2α, and 12 h later the structural luteolysis is performed (Neuvias et al., 2004a; b; Mishra et al., 2018).
CL FUNCTIONAL REGRESSION
ON prevents the synthesis and secretion of progesterone by inhibiting the expression of the StAR protein, as well as the fragmenting enzymes of the cytochrome P450scc and 3- βHSD side chain (Sessa et al., 1994; Sawada and Carlson, 1996; Skarzynski and Okuda, 2000; Korzekwa et al., 2004, 2006; 2007; 2014; Girsh et al., 1995; 1996a, b; Skarzynski et al., 2003a; b; Rekawiecki et al., 2005). Consequently, cholesterol cannot enter the mitochondria and the available cholesterol within it will not be transformed into pregnenolone, and will not become progesterone. The level of progesterone decreases to a baseline concentration and the negative feedback on the hypothalamus-pituitary axis will be removed, another zeal will be presented and a new opportunity of pairing and conceive.
CL STRUCTURAL REGRESSION
The structural regression of CL is performed by apoptosis and physiological necrosis of steroidogenic luteal cells (Juengel et al., 1993; Rueda et al., 1995, 1997a; b; Tilly, 1996; Korzekwa et al., 2006; Park et al. 2017).
Apoptosis
Apoptosis is the programmed cell death in a physiological model, where the cell designs and executes its own death. It is performed through genetically encoded cell collapse with cellular shrinkage; protein disintegration, chromatin condensation and DNA degradation; in addition to cell fragmentation and formation of apoptotic bodies. Finally, neighboring cells such as fibroblasts or epithelial cells, phagocytize apoptotic bodies without triggering an inflammatory reaction (Compton, 1992).
La apoptosis se realiza por medio de las caspasas (Clarke, 1990; Clark y Lampert 1990; Tilly, 1996; Carambula et al., 2002); las cuales se han considerado como sus ejecutoras que participan como iniciadoras y ejecutoras del proceso (Cohen, 1997). La lutéolisis se lleva a cabo en las células lúteas esteroidogénicas (SLC) y en las células lúteas endoteliales (LEC) (Juengel et al., 1993; Rueda et al., 1995; 1997a,b). Su actividad la llevan a cabo principalmente a través de una vía extrínseca, por un dominio de muerte o receptor, y por vía intrínseca de tipo mitocondrial.
Extrinsic via
The extrinsic via is executed by a wide variety of factors involved in apoptosis (Friedman et al., 2000; Petroff et al., 2001; Taniguchi et al., 2002; Okuda et al., 2004; Korzekwa et al., 2006; Hojo et al., 2010; 2016) as the tumor necrosis factor α (TNF), interferon-γ (IFNG), FAS ligand (FASL) and nitric oxide (NO) (Friedman et al., 2000; Petroff et al ., 2001; Nakamura and Sakamoto, 2001; Taniguchi et al., 2002; Korzekwa et al., 2006; Hojo et al., 2010; 2016). These factors have also been found to participate in the vascular regression of CL; for example, the type 1 TNF receptor (TNFR1); as well as the related protein called Fas (CD95) and its ligand (Fas ligand); they have intracellular death domains that recruit adapter proteins such as the death domain associated with the TNF receptor (TRADD) and the death domain associated with Fas (FADD); also, cysteine proteases such as caspases. The binding of the death ligand with its corresponding receptor leads to the formation of a binding site for the adapter protein, as a consequence a ligand-receptor-adapter complex known as DISC (signaling complex that induces death) is formed. This assembles and activates pro-caspase 8, with the subsequent constitution of caspase-8, an active form of the enzyme that will constitute the initiating caspase and establishing the caspase cascade. In the cow's CL, TNF is located (Sakumoto et al., 2011), and induces interferon-γ and Fas in the apoptosis process, by increasing the activation of caspase-3 (Taniguchi et al., 2002); which is finally the effector molecule (Nagata, 1997; Muzio et al., 1998).
Intrinsic via
The intrinsic pathway begins within the cell through internal stimuli such as hypoxia; Caspase is activated during apoptosis at the mitochondrion level, which stimulates the union of pro-apoptosis caspase with mitochondria, and inhibits the association of anti- apoptosis Bcl-2. This leads to the filtration of cytochrome-c from the mitochondria into the cytosol, which promotes the formation of apoptosome and triggers the activation of the Caspasa effector (Scaffidi et al., 1998). In the Bcl family there are two groups; pro- apoptotic proteins, such as Bax and anti-apoptotic, such as Bcl-2. Its function as noted, is related to the release of cytochrome-c, for the formation of apoptosome, and to activate caspase. Pro and anti-apoptotics release and slow the release of cytochrome-c from the mitochondria into the cytoplasm, respectively. Based on the above, the activation of the deadly pathway involves the release of cytochrome-c within the cytosol, which in turn promotes the formation of apoptosome and activation of the effector caspase-3, with subsequent DNA fragmentation (Thorneberry and Lazebnik, 1998), in the final step of apoptosis (Scaffidi et al., 1998).
The participation of ON is done through the stimulation of Bax propoptotic expression, with no effect on the expression of Fas and Bcl-2 RNAm (Korzekwa et al., 2006). Consequently, the ratio of Bcl-2 to bax decreases, ratio of Bcl-2 mRNA and Bax mRNA in bovine CL, decreases in luteolysis; In addition, in these cells in vitro, ON stimulates the expression and activity of caspase-3 (Skarzynski et al., 2005; Korzekwa et al., 2006). ON also increases the production of intraluteal PGF2α and reduces the expression of mRNA superoxide dismutase (SOD) and its protein in 24-hour culture of bovine LECs (Lee et al., 2010). The increase in intraluteal PGF constitutes an amplification system, where a small stimulus triggers a series of reactions that increase the cellular response; in this way it increases its function, and the reduction of SOD to increase intraluteal super oxide. The reduction of SOD at 24 h could increase the intraluteal accumulation of SO for the promotion of structural luteolysis (Nakamura and Sakumoto, 2001; Buttke and Sandstrom, 1994; Rothstein et al., 1994; Suhara et al., 1998). SOD catalyzes the dismutation of superoxide to H2O2 and oxygen, and as a consequence keeps it below the level of superoxide (Fridovich, 1995).
Necroptosis
Apoptosis can be performed by a mechanism independent of caspases, as an alternate route for cell death or necroptosis and is carried out by receptors that interact with protein kinase (RIPK) such as 1 (RIPK1) and 3 (RIPK3 ) (Festjens et al., 2007; Hitomi et al., 2008; Degterev et al., 2008; Degterev et al., 2008; Declercq et al., 2009; Cho et al., 2009; He et al., 2009 ; Zhang et al., 2009; Christofferson and Yuan, 2010; Vandenabeele et al., 2010). RIPK1 binds to the membrane of TNFR1 and FAS; Apoptosis inducing ligand receptors TNF1 (TRAILR1) and 2 (TRAILR2), to trigger the necroptotic pathway of members of the TNF receptor super family (Holler et al., 2000). RIPK3 is a necessary modulator for necroptosis, but particularly TNFR1 and FAS. (Taniguchi et al., 2002; Cho et al., 2009; He et al., 2009; Zhang et al., 2009; Vanlangerakker et al., 2012). (Zhang et al., 2009; Vanlangerakker et al., 2012; Moujalled et al., 2013). Necroptosis-dependent RIPKs participate in bovine structural luteolysis (Christofferson and Yuan, 2010; Vandenabeele et al., 2010).
BLOOD IRRIGATION
Prostaglandin F2α participates in vasodilation and in the vasoconstriction of CL (Wiltbank et al., 1995; Díaz et al., 2002); in spontaneous luteolysis and application of exogenous F2α prostaglandin, an increase in blood flow continues in the periphery of the corpus luteum (Acosta et al., 2002; Miyamoto et al., 2005; Ginther et al., 2007; Miyamoto and Shirasuna, 2009; Shirasuna et al., 2012). This is due to the ON which has vasodilator capacity and directly inhibits the secretion of progesterone, inducing apoptosis of the luteal cells (Skarzynski et al., 2003a, b; Shirasuna et al., 2008a, b, c; Shirasuna et al., 2012). The effect of prostaglandin on the secretion of ON and the acute increase in blood flow at the periphery of the corpus luteum has been considered the first physiological indicator of luteolysis (Shirasuna et al., 2008a, b, c; 2010; 2012). The influence of prostaglandin F2α on nitric oxide has been proven by its effect on intermediates.
The application of prostaglandin F2α stimulates the endothelial expression of nitric oxide synthase (enzyme responsible for transforming L-arginine into nitric oxide) in the corpus luteum, 30 minutes after its application, with the corresponding increase in luteal blood flow (Shirasuma et al ., 2008a, b, c). On the other hand, the effect of nitric oxide on blood flow has been demonstrated through its promotion and inhibition. The supplier of nitric oxide (S-nitroso-N-acetyl-D, L-pellicilamine) in the corpus luteum, induces an acute increase in blood flow and shortens the estrous cycle. In addition, the injection of nitric oxide synthase inhibitor (L-NG-nitroarginine methyl ester) into the corpus luteum completely suppresses the acute increase in blood flow caused by prostaglandin F2α, and delays the onset of luteolysis (Shirasuma et al., 2008b).
Prostaglandin F2α, after its vasodilator effect, limits the supply of oxygen and nutrients to the corpus luteum to culminate luteolysis by inhibiting angiogenesis, angiolysis and vasoconstriction (Guilbault et al., 1984; Acosta et al., 2002). Thirty minutes after the injection of prostaglandin F2α in the middle part of the cycle; down regulation of RNAm expression of vascular endothelial growth factor and basic trophoblastic growth factor has been observed; as well as the protein expression of vascular endothelial growth factor A (Berisha et al., 2008; Shirasuna et al., 2010). With this, prostaglandin F2α inhibits the development of thin and subsequently thick blood vessels (Hojo et al., 2009).
Prostaglandin F2α stimulates the biosynthesis of endothelin-1 (EDN1) and the expression of its RNAm; as well as angiotensin II (Ang II) and the expression of the angiotensin- converting enzyme, both in vivo and in vitro (Girsh et al., 1996b ; Miyamoto et al., 1997; Hayashi and Miyamoto, 1999). These are potent vasoconstrictors that operate in response to prostaglandin F2α to reduce blood supply, and therefore decrease the availability of oxygen and nutrients to the corpus luteum during luteolysis (Girsh et al., 1996a; Miyamoto et al., 1997; Hayashi and Miyamoto, 1999). EDN1 and Ang II have also been found to inhibit progesterone secretion in the corpus luteum in vitro (Stirling et al., 1990; Girsh et al., 1996a; Miyamoto et al., 1997), which places them as factors that they participate in functional luteolysis.
Circulating concentrations of progesterone are determined by a balance between primary production of P4, by the CL; and the metabolism of P4, by the liver. The volume of the luteal tissue, the number and functionality of the large luteal cells are the main factors that determine the production of the hormone progesterone (Gregson et al., 2016). The metabolic rate of P4 is usually determined by hepatic blood flow and can be very important, especially in dairy cows, to determine the circulating concentrations of progesterone (P4).
By performing artificial time insemination (IATF), it has been possible to increase the concentrations of P4, by increasing the number of CLs, inducing the appearance of an accessory CL, or by supplementing exogenous sources of the P4 hormone. Controlling the diet can also modify P4 concentrations; however, there are still no practical strategies that allow altering P4 in the diet at the field level and in a practical way. By raising P4 before artificial fixed-time insemination (IATF), double ovulations are generally reduced and fertility of fixed-time insemination is increased. By raising P4 at the time of AI, it generates slight increases in circulating P4, possibly due to an inadequate luteal regression that could compromise fertility in response to AI. By raising P4 after AI, circulating levels of P4 are critical for embryonic growth and the establishment and maintenance of pregnancy. Several studies have attempted to increase fertility by increasing circulating levels of P4 after IATF. There is a meta-analysis that indicates a slight increase in fertility (3 to 3.5 %), mainly in first-birth cows (Wiltbank et al., 2014). Future research should focus on manipulating P4 in the cow to ensure greater success in reproductive function.
CONCLUSION
The ovarian corpus luteum is an ephemeral life gland that produces the hormone progesterone. Progesterone exerts negative feedback on the hypothalamus and pituitary gland to reduce gonadotropin secretion to avoid ovulations. In cows that do not conceive PGF2α, it regresses, which reduces the secretion of progesterone to levels that were recorded before its formation. The regression of the corpus luteum is functional and structural. In the functional regression the synthesis and secretion of progesterone is prevented, but the structural regression is carried out by means of apoptosis and necroptosis of the steroidogenic luteal cells. PGF2α participates in the irrigation of the corpus luteum by providing nutrients. Therefore, in future research, the manipulation of circulating prostaglandins should be concentrated to ensure greater reproductive success, mainly when fixed or predetermined insemination programs are applied in bovine females.