Developmental and tumoral vascularization is regulated by G protein-coupled receptor kinase 2

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.Our laboratory is funded by grants from Ministerio de Educación y Ciencia (SAF2011-23800), Fundación Ramón Areces, The Cardiovascular Network (RECAVA) of Ministerio Sanidad y Consumo-Instituto Carlos III (RD06-0014/0037 and RD12/0042/0012), and Comunidad de Madrid (S-2010/BMD- 2332) to F. Mayor Jr. and Instituto Carlos III (PI11/00859), Fundación Ramón Areces, and Fundación Rodríguez Pascual to P. Penela. Marta Mendiola is supported by a postdoctoral research contract from Fondo de Investigación Sanitaria (“Sara Borrell” Programme), Instituto de Salud Carlos III

Effects of the intensity of prehospital treatment on short-term outcomes in patients with acute heart failure. the SEMICA-2 study

Objective: Little is known about treatments provided by advanced life support (ALS) ambulance teams to patients with acute heart failure (AHF) during the prehospital phase, and their influence on short-term outcome. We evaluated the effect of prehospital care in consecutive patients diagnosed with AHF in Spanish emergency departments (EDs). Methods: We selected patients from the EAHFE registry arriving at the ED by ALS ambulances with available follow-up data. We recorded specific prehospital ALS treatments (supplemental oxygen, diuretics, nitroglycerin, non-invasive ventilation) and patients were grouped according to whether they received low- (LIPHT; 0/1 treatments) or high-intensity prehospital therapy (HIPHT; > 1 treatment) for AHF. We also recorded 46 covariates. The primary endpoint was all-cause 7-day mortality, and secondary endpoints were prolonged hospitalisation (> 10 days) and in-hospital and 30-day mortality. Unadjusted and adjusted odds ratios were calculated to compare the groups. Results: We included 1493 patients [mean age 80.7 (10) years; women 54.8%]. Prehospital treatment included supplemental oxygen in 71.2%, diuretics in 27.9%, nitroglycerin in 13.5%, and non-invasive ventilation in 5.3%. The LIPHT group included 1041 patients (70.0%) with an unadjusted OR for 7-day mortality of 1.770 (95% CI 1.115–2.811; p = 0.016), and 1.939 (95% CI 1.114–3.287, p = 0.014) after adjustment for 16 discordant covariables. The adjusted ORs for all secondary endpoints were always > 1 in the LIPHT group, but none reached statistical significance. Conclusions: Patients finally diagnosed with AHF at then ED that have received LIPHT by the ALS ambulance teams have a poorer short-term outcome, especially during the first 7 days