6533b862fe1ef96bd12c6c63
RESEARCH PRODUCT
Developmental and tumoral vascularization is regulated by G protein-coupled receptor kinase 2
Verónica RivasVerónica RivasLaura NoguésLaura NoguésRamón Muñoz-chápuliFederico MayorFederico MayorRita CarmonaMarta MendiolaRamón García-escuderoDavid HardissonMaría Miguel-martínGerald W. DornClara RegleroClara RegleroPetronila PenelaPetronila Penelasubject
medicine.medical_specialtyG-Protein-Coupled Receptor Kinase 2Angiogenic SwitchAngiogenesisMedicinaActivin Receptors Type IIMelanoma ExperimentalReceptor Transforming Growth Factor-beta Type INeovascularization PhysiologicProtein Serine-Threonine KinasesBiologyMural cellGrk2Transforming Growth Factor beta1NeovascularizationMiceDownregulation and upregulationCell MovementPregnancyInternal medicinemedicineAnimalsHumansCell ProliferationHemizygoteMice KnockoutG protein-coupled receptor kinaseTumorNeovascularization PathologicEndothelial CellsRetinal VesselsG proteinGeneral MedicineCell biologyEndocrinologymedicine.anatomical_structurecardiovascular systemFemalePericyteSignal transductionmedicine.symptomActivin Receptors Type IReceptors Transforming Growth Factor betaSignal TransductionResearch Articledescription
Tumor vessel dysfunction is a pivotal event in cancer progression. Using an in vivo neovascularization model, we identified G protein–coupled receptor kinase 2 (GRK2) as a key angiogenesis regulator. An impaired angiogenic response involving immature vessels was observed in mice hemizygous for Grk2 or in animals with endothelium-specific Grk2 silencing. ECs isolated from these animals displayed intrinsic alterations in migration, TGF-β signaling, and formation of tubular networks. Remarkably, an altered pattern of vessel growth and maturation was detected in postnatal retinas from endothelium-specific Grk2 knockout animals. Mouse embryos with systemic or endothelium-selective Grk2 ablation had marked vascular malformations involving impaired recruitment of mural cells. Moreover, decreased endothelial Grk2 dosage accelerated tumor growth in mice, along with reduced pericyte vessel coverage and enhanced macrophage infiltration, and this transformed environment promoted decreased GRK2 in ECs and human breast cancer vessels. Our study suggests that GRK2 downregulation is a relevant event in the tumoral angiogenic switch.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2012-10-12 |