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1.
Angiogenesis ; 26(3): 365-384, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-36631598

RESUMO

The Feline Leukemia Virus Subgroup C Receptor 1a (FLVCR1a) is a transmembrane heme exporter essential for embryonic vascular development. However, the exact role of FLVCR1a during blood vessel development remains largely undefined. Here, we show that FLVCR1a is highly expressed in angiogenic endothelial cells (ECs) compared to quiescent ECs. Consistently, ECs lacking FLVCR1a give rise to structurally and functionally abnormal vascular networks in multiple models of developmental and pathologic angiogenesis. Firstly, zebrafish embryos without FLVCR1a displayed defective intersegmental vessels formation. Furthermore, endothelial-specific Flvcr1a targeting in mice led to a reduced radial expansion of the retinal vasculature associated to decreased EC proliferation. Moreover, Flvcr1a null retinas showed defective vascular organization and loose attachment of pericytes. Finally, adult neo-angiogenesis is severely affected in murine models of tumor angiogenesis. Tumor blood vessels lacking Flvcr1a were disorganized and dysfunctional. Collectively, our results demonstrate the critical role of FLVCR1a as a regulator of developmental and pathological angiogenesis identifying FLVCR1a as a potential therapeutic target in human diseases characterized by aberrant neovascularization.


Assuntos
Células Endoteliais , Neoplasias , Adulto , Animais , Humanos , Camundongos , Células Endoteliais/fisiologia , Neovascularização Patológica/genética , Neovascularização Fisiológica/genética , Peixe-Zebra
2.
Biomed Res Int ; 2017: 2682861, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29214163

RESUMO

Pyridoxamine, a structural analog of vitamin B6 that exerts antiglycative effects, has been proposed as supplementary approach in patients with initial diabetic nephropathy. However, the molecular mechanism(s) underlying its protective role has been so far slightly examined. C57Bl/6J mice were fed with a standard diet (SD) or a diet enriched in fat and fructose (HD) for 12 weeks. After 3 weeks, two subgroups of SD and HD mice started pyridoxamine supplementation (150 mg/kg/day) in the drinking water. HD fed mice showed increased body weight and impaired glucose tolerance, whereas pyridoxamine administration significantly improved insulin sensitivity, but not body weight, and reduced diet-induced increase in serum creatinine and urine albumin. Kidney morphology of HD fed mice showed strong vacuolar degeneration and loss of tubule brush border, associated with a drastic increase in both advanced glycation end products (AGEs) and AGEs receptor (RAGE). These effects were significantly counteracted by pyridoxamine, with consequent reduction of the diet-induced overactivation of NF-kB and Rho/ROCK pathways. Overall, the present study demonstrates for the first time that the administration of the antiglycative compound pyridoxamine can reduce the early stages of diet-dependent kidney injury and dysfunction by interfering at many levels with the profibrotic signaling and inflammatory cascades.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Substâncias Protetoras/farmacologia , Piridoxamina/farmacologia , Albuminas/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Creatinina/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/urina , Dieta/métodos , Suplementos Nutricionais , Gorduras/administração & dosagem , Frutose/administração & dosagem , Intolerância à Glucose/sangue , Intolerância à Glucose/tratamento farmacológico , Intolerância à Glucose/metabolismo , Intolerância à Glucose/urina , Produtos Finais de Glicação Avançada/metabolismo , Resistência à Insulina/fisiologia , Rim , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Insuficiência Renal/tratamento farmacológico , Insuficiência Renal/urina , Aumento de Peso/efeitos dos fármacos
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