RESUMO
Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are quintessential for the development and maintenance of blood and lymphatic vessels. However, genetic interactions between the VEGFRs are poorly understood. VEGFR2 is the dominant receptor that is required for the growth and survival of the endothelium, whereas deletion of VEGFR1 or VEGFR3 was reported to induce vasculature overgrowth. Here we show that vascular regression induced by VEGFR2 deletion in postnatal and adult mice is aggravated by additional deletion of VEGFR1 or VEGFR3 in the intestine, kidney, and pancreas, but not in the liver or kidney glomeruli. In the adult mice, hepatic and intestinal vessels regressed within a few days after gene deletion, whereas vessels in skin and retina remained stable for at least four weeks. Our results show changes in endothelial transcriptomes and organ-specific vessel maintenance mechanisms that are dependent on VEGFR signaling pathways and reveal previously unknown functions of VEGFR1 and VEGFR3 in endothelial cells.
Assuntos
Vasos Sanguíneos/fisiologia , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismo , Fatores Etários , Animais , Apoptose , Células Endoteliais/metabolismo , Endotélio/metabolismo , Deleção de Genes , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Camundongos , Camundongos Knockout , Densidade Microvascular/genética , Família Multigênica , Neovascularização Fisiológica/genética , Especificidade de Órgãos/genética , Fenótipo , Ligação Proteica , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Transdução de Sinais , Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
BACKGROUND: Pulmonary hypertension (PH) is a common complication in patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a severe congenital disorder associated with mutations in the FOXF1 gene. Although the loss of alveolar microvasculature causes PH in patients with ACDMPV, it is unknown whether increasing neonatal lung angiogenesis could prevent PH and right ventricular (RV) hypertrophy. METHODS: We used echocardiography, RV catheterization, immunostaining, and biochemical methods to examine lung and heart remodeling and RV output in Foxf1WT/S52F mice carrying the S52F Foxf1 mutation (identified in patients with ACDMPV). The ability of Foxf1WT/S52F mutant embryonic stem cells to differentiate into respiratory cell lineages in vivo was examined using blastocyst complementation. Intravascular delivery of nanoparticles with a nonintegrating Stat3 expression vector was used to improve neonatal pulmonary angiogenesis in Foxf1WT/S52F mice and determine its effects on PH and RV hypertrophy. RESULTS: Foxf1WT/S52F mice developed PH and RV hypertrophy after birth. The severity of PH in Foxf1WT/S52F mice directly correlated with mortality, low body weight, pulmonary artery muscularization, and increased collagen deposition in the lung tissue. Increased fibrotic remodeling was found in human ACDMPV lungs. Mouse embryonic stem cells carrying the S52F Foxf1 mutation were used to produce chimeras through blastocyst complementation and to demonstrate that Foxf1WT/S52F embryonic stem cells have a propensity to differentiate into pulmonary myofibroblasts. Intravascular delivery of nanoparticles carrying Stat3 cDNA protected Foxf1WT/S52F mice from RV hypertrophy and PH, improved survival, and decreased fibrotic lung remodeling. CONCLUSIONS: Nanoparticle therapies increasing neonatal pulmonary angiogenesis may be considered to prevent PH in ACDMPV.
Assuntos
Técnicas de Transferência de Genes , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/terapia , Nanopartículas , Síndrome da Persistência do Padrão de Circulação Fetal/complicações , Alvéolos Pulmonares/anormalidades , Fator de Transcrição STAT3/genética , Remodelação das Vias Aéreas/genética , Animais , Biomarcadores , Modelos Animais de Doenças , Suscetibilidade a Doenças , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Ecocardiografia , Fibrose , Fatores de Transcrição Forkhead/deficiência , Terapia Genética , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/metabolismo , Hipertrofia Ventricular Direita/diagnóstico , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/metabolismo , Camundongos , Camundongos Transgênicos , Densidade Microvascular/genética , Miofibroblastos/metabolismo , Síndrome da Persistência do Padrão de Circulação Fetal/genética , Síndrome da Persistência do Padrão de Circulação Fetal/patologia , Fator de Transcrição STAT3/administração & dosagem , Nanomedicina Teranóstica/métodos , Resultado do Tratamento , Remodelação Vascular/genéticaRESUMO
PURPOSE: To detect protein expressions of insulin-like growth factor II messenger ribonucleic acid-binding protein 3 (IMP3) and vascular endothelial growth factor (VEGF) in osteosarcoma tissues and explore the relationships of protein expressions of IMP3 and VEGF with stage, microvessel density (MVD) and pulmonary metastasis of osteosarcoma patients. METHODS: Immunohistochemical staining was used to detect protein expressions of IMP3 and VEGF in 37 cases of osteosarcoma, and their correlations with stage, MVD and pulmonary metastasis of osteosarcoma patients were analyzed in combination with clinical data. RESULTS: Protein expressions of IMP3 and VEGF in osteosarcoma were significantly higher than those in normal tissues adjacent to the tumor (p<0.05, p<0.05). The distribution of stage III in osteosarcoma patients with high protein expressions of IMP3 and VEGF increased. With the enhancement of protein expressions of IMP3 and VEGF, MVD elevated, the probability of pulmonary metastasis increased, and the survival time decreased markedly in osteosarcoma patients. CONCLUSIONS: High expressions of IMP3 and VEGF are positively correlated with stage, MVD and pulmonary metastasis of osteosarcoma, and can be applied as potential indicators of the malignant degree of osteosarcoma and the prognosis of patients.