RESUMO
Numerous studies have suggested a link between the angiogenic FGF and VEGF signaling pathways; however, the nature of this link has not been established. To evaluate this relationship, we investigated VEGF signaling in ECs with disrupted FGF signaling in vitro and in vivo. ECs lacking FGF signaling became unresponsive to VEGF, caused by downregulation of VEGF receptor 2 (VEGFR2) expression after reduced Vegfr2 enhancer activation. FGF mediated VEGFR2 expression via activation of Erk1/2. Transcriptional analysis revealed that Ets transcription factors controlled VEGFR2 expression in an FGF- and Erk1/2-dependent manner. Mice with defective FGF signaling exhibited loss of vascular integrity and reduced vascular morphogenesis. Thus, basal FGF stimulation of the endothelium is required for maintenance of VEGFR2 expression and the ability to respond to VEGF stimulation and accounts for the hierarchic control of vascular formation by FGFs and VEGF.
Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Células Cultivadas , Células Endoteliais/citologia , Células Endoteliais/fisiologia , Ativação Enzimática , Fatores de Crescimento de Fibroblastos/genética , Membro Posterior/irrigação sanguínea , Membro Posterior/patologia , Humanos , Isquemia/metabolismo , Isquemia/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neovascularização Fisiológica/fisiologia , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/metabolismo , Transdução de Sinais/fisiologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
BACKGROUND: Adenosine has been available for use in myocardial perfusion single-photon emission computed tomography (SPECT) in Japan since 2005. The purpose of this study was to evaluate the safety of and tolerance to thallium-201 myocardial perfusion SPECT with intravenous adenosine infusion in Japanese patients with suspected coronary artery disease. METHODS AND RESULTS: Two hundred and six consecutive patients who underwent an adenosine infusion (120 mug . kg(-1) . min(-1)) SPECT at Sumitomo Besshi Hospital (Niihama, Japan) were investigated. The effects of adenosine infusion were monitored for each patient. A coronary angiography was performed in 81 patients. Adenosine infusion significantly decreased blood pressure and increased heart rate. Adverse reactions were observed in 161 patients (78.2%). Most reactions were transient, disappearing soon after the termination of adenosine infusion. No serious adverse reactions, such as acute myocardial infarction or death, occurred. Adenosine infusion was terminated in 3 patients (1.5%) because of near syncope or sustained 2:1 atrioventricular block. Electrocardiographic changes occurred in 15 patients (7.3%). Self-assessed scoring after SPECT showed that the patients were very tolerant (74.6% of 177 patients) of adenosine infusion myocardial SPECT. The sensitivity and specificity were 75.0% and 69.7%, respectively. CONCLUSIONS: Adenosine infusion myocardial SPECT is safe and well tolerated in the Japanese population, despite the frequent occurrence of minor adverse reactions.