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Modulación de la actividad del receptor de proteína morfogenética ósea endotelial tipo 2 por el receptor de factor de

Cheol Hwangbo¹, Heon-Woo Lee¹, Hyeseon Kang¹

¹From Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (C.H., H.-W.L., H.K., H.J., I.P., J.H., J.-D.K., W.P.D., X.H., S.L., O.E.-H., A.S., H.J.C., S.-W.J.); Department of Biology, University of North Carolina, Chapel Hill (D.S.W., V.L.B.); School of Life Sciences and Cell Logistics Research Center, Gwangju Institute of Science and Technology, Korea (B.P., S.-W.J.); Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, OH (L.P., S.C., S.C.E.); Center for Functional Connectomics, Korea Institute of Science and Technology, Seoul (E.M.H., J.-Y.P.); School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul (J.-Y.P.); Department of Neurology, Yale University School of Medicine, New Haven, CT (J.-L.T.); and Université Pierre and Marie Curie-Paris 6, CRICM, Groupe Hospitalier Pitié-Salpètrière, France; INSERM, UMRS 975, Groupe Hospitalier Pitié-Salpètrière, Paris, France; APHP, Groupe Hospitalier Pitié-Salpètrière, Paris, France (J.-L.T.).

|March 31, 2017

Resumen

El receptor 3 del factor de crecimiento endotelial vascular (VEGFR3) regula la señalización del receptor de proteína morfogénica ósea tipo 2 (BMPR2), lo que influye en el desarrollo de la hipertensión arterial pulmonar (HAP). La restauración de VEGFR3 en las células de HAP mejoró la señalización de BMP, identificando a VEGFR3 como un factor clave en la HAP.

Área de la Ciencia:

Biología cardiovascular
La medicina molecular
Biología de las células endoteliales

Sus antecedentes:

La señalización de la proteína morfogénica ósea (BMP) es crucial para el desarrollo y la función vascular.
Las mutaciones en el receptor BMP tipo 2 (BMPR2) son comunes en la hipertensión arterial pulmonar familiar (HAP), pero no todos los portadores desarrollan la enfermedad.
Esto sugiere que otros factores modifican la función de la BMPR2 e influyen en la aparición y progresión de la HAP.

Objetivo del estudio:

Investigar la interacción entre el receptor 3 del factor de crecimiento endotelial vascular (VEGFR3) y el BMPR2.
Determinar el papel de VEGFR3 en la señalización de BMP y su impacto en la hipertensión pulmonar.

Principales métodos:

Estudio en embriones de pez cebra y ratones con deleción específica del endotelio de Vegfr3.
Estudios in vitro con células endoteliales humanas, incluidas las células endoteliales pulmonares primarias de pacientes con HAP.
Se evaluó la asociación física entre VEGFR3 y BMPR2 y los eventos de señalización posteriores.

Principales resultados:

La atenuación de Vegfr3 en peces cebra alteró la angiogénesis inducida por BMP.
Las células endoteliales que carecen de VEGFR3 mostraron una respuesta alterada a la estimulación de BMP.
VEGFR3 interactúa físicamente con BMPR2, facilitando su endocitosis y la posterior fosforilación de SMAD.
La deleción endotelial de Vegfr3 en ratones empeoró la hipertensión pulmonar inducida por hipoxia.
Se observó una reducción de la expresión de VEGFR3 en las células endotelial arterial pulmonar humana.
El restablecimiento de VEGFR3 en las células de HAP normalizó la señalización de BMP.

Conclusiones:

El VEGFR3 es un regulador crítico de la señalización BMPR2 endotelial.
Los niveles de expresión de VEGFR3 pueden ser determinantes de la penetración de HAP en individuos con mutaciones de BMPR2.

Palabras clave:

Proteína FLT4 humana Receptores de proteínas morfogenéticas óseas, tipo II células endoteliales hipertensión pulmonar

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