Developmental and tumoral vascularization is regulated by G protein–coupled receptor kinase 2
Verónica Rivas, … , Federico Mayor Jr., Petronila Penela
Verónica Rivas, … , Federico Mayor Jr., Petronila Penela
Published October 25, 2013
Citation Information: J Clin Invest. 2013;123(11):4714-4730. https://doi.org/10.1172/JCI67333.
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Developmental and tumoral vascularization is regulated by G protein–coupled receptor kinase 2

Abstract

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.

Authors

Verónica Rivas, Rita Carmona, Ramón Muñoz-Chápuli, Marta Mendiola, Laura Nogués, Clara Reglero, María Miguel-Martín, Ramón García-Escudero, Gerald W. Dorn II, David Hardisson, Federico Mayor Jr., Petronila Penela

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Figure 1

GRK2 deficiency results in an impaired in vivo angiogenesis, despite effective EC activation.

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GRK2 deficiency results in an impaired in vivo angiogenesis, despite eff...
(A) Matrigel implants mixed with the indicated stimuli or vehicle were injected into WT (Grk2+/+) or global hemizygous (Grk2+/–) mice, and hemoglobin content was quantified as described in the Methods. The angiogenic response data (calculated as fold over control conditions) were obtained from 9 to 12 animals for each condition in 3 to 4 independent experiments. (B) GRK2 downregulation does not compromise the S1P-induced activation of ERK1/2 and AKT pathways in MLECs. Data from 3 to 4 independent experiments are shown. Representative blots are shown. (C and D) GRK2 downmodulation enhances the PI3K-dependent directed cell migration of ECs in response to fibronectin (FN) and S1P. Data of 4 to 6 independent experiments performed in duplicate are shown. ERK1/2 and AKT activation and cell migration assays are detailed in Methods.