Increased ocular levels of IGF-1 in transgenic mice lead to diabetes-like eye disease

Ruberte, Jesús; Ayuso, Eduard; Navarro, Marc; Carretero, Ana; Nacher, Víctor; Haurigot, Virginia; George, Mónica; Llombart, Cristina; Casellas, Alba; Costa, Cristina; Bosch, Assumpcio; Bosch, Fátima

doi:10.1172/jci19478

Cited by 148 publications

(126 citation statements)

References 57 publications

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“…Our observations showing decreased levels of Foxf1 and Foxf2 mRNA in Lif, Igf-I, and Lif/Igf-I knockouts would support alterations in mesenchymal and vasculogenesis maturation mediated by IGF-I and LIF. Although LIF function in vasculogenesis is poorly known, these results are consistent with previous reports linking IGF-I and angiogenesis in tissues such as brain and retina (Hellstrom et al, 2001;LopezLopez et al, 2004;Ruberte et al, 2004). Blocking IGF-IR signalling in lung explants, in addition to reduced lung growth and branching of the epithelium, resulted in an inhibition of endothelial cell development (Han et al, 2003).…”

Section: Discussionsupporting

confidence: 89%

Alterations in alveolar epithelium differentiation and vasculogenesis in lungs of LIF/IGF‐I double deficient embryos

Moreno-Barriuso¹,

López-Malpartida²,

Pablo³

et al. 2006

Developmental Dynamics

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Previous studies on double deficient mice for leukemia inhibitory factor (LIF) and insulin-like growth factor I (IGF-I) reported that they died of respiratory failure, with abnormal lung histology and altered expression of pulmonary markers. Here we analyzed prenatal Lif/Igf-I double mutant mouse embryos to characterize LIF and IGF-I cooperative roles in distal lung epithelium and vascular maturation. Lungs of IGF-I-deficient embryos displayed a higher proportion of type II pneumocytes, less differentiated type I pneumocytes, and failure in alveolar capillary remodeling compared to wild type and LIF-deficient mice. Lif/Igf-I double knockout lungs showed aggravated pulmonary hypoplasia, lower airway volume, increased proliferation, and elevated levels of ERK1/2 activation. In addition, their alveoli were collapsed and lined by type II cells. The differentiation of type I cells barely occurred and capillaries remained in the abundant mesenchyme. These results indicate that LIF collaborates with IGF-I in lung alveolar epithelium and vascular maturation.

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Section: Discussionsupporting

confidence: 89%

Alterations in alveolar epithelium differentiation and vasculogenesis in lungs of LIF/IGF‐I double deficient embryos

Moreno-Barriuso¹,

López-Malpartida²,

Pablo³

et al. 2006

Developmental Dynamics

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“…Glucose levels did not differ significantly between wt and trVEGF029 (wt: 5.36±0.99 mmol/l; trVEGF029: 5.42± 0.90 mmol/l; p>0.05) and were similar to those in the aqueous humour of an IGF-1 transgenic mouse [30].…”

Section: Retinal Trypsin Digestion For Quantification Of Endothelial mentioning

confidence: 71%

Long-term global retinal microvascular changes in a transgenic vascular endothelial growth factor mouse model

et al. 2006

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Aims/hypothesis: Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of diabetic retinopathy. We investigated whether transgenic mice with moderate VEGF expression in photoreceptors (trVEGF029) developed changes similar to diabetic retinopathy and whether retinopathy progressed with time. Materials and methods: Human VEGF 165 (hVEGF 165 ) expression was analysed using ELISA and quantitative RT-PCR; serum glucose levels were also measured. Fundus fluorescein angiography (FA) was used to screen the degree of retinopathy from 6 weeks. Dynamic changes in the density of retinal microvasculature, as well as other changes similar to diabetic retinopathy, including retinal leucostasis, capillary endothelial cell and pericyte loss, and numbers of acellular capillaries, were quantified. Results: trVEGF029 mice were normoglycaemic and showed a moderate, short-term hVEGF 165 upregulation for up to 3 weeks. Changes in the retinal microvasculature not only mimicked those seen in diabetic retinopathy, but also showed similar pathological progression with time. FA at 6 weeks identified two phenotypes, mild and moderate, which were distinguished by the extent of vascular leakage. Quantitative analysis of diabetic retinopathy-like changes revealed that these parameters were tightly correlated with the initial degree of vascular leakage; low levels reflected slow and limited retinal microvascular changes in mild cases and high levels reflected more rapid and extensive changes in moderate cases. Conclusions/interpretation: The data suggest that even an early short-term elevation in hVEGF 165 expression might set a train of events that lead to progressive retinopathy. Induction of many features characteristic of diabetic retinopathy in trVEGF029 enables mechanisms leading to the disease state to be examined, and provides a relevant animal model for testing novel therapeutics.

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“…Early studies suggested that GH-deficient patients with diabetes were protected from retinopathy, and pituitary ablation, which decreases GH levels, was a treatment for severe retinopathy before the advent of laser photocoagulation. Overexpression of IGF1 in the retina resulted in changes similar to those of diabetic retinopathy (Ruberte et al 2004). Subsequently, intraocular overexpression of IGF1 has been shown to result in breakdown of the blood-retinal barrier and increased retinal vascular permeability (Haurigot et al 2009).…”

Section: Diabetic Retinopathymentioning

confidence: 98%

Endothelial cells and the IGF system

Bach¹

2014

Journal of Molecular Endocrinology

152

118

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Endothelial cells line blood vessels and modulate vascular tone, thrombosis, inflammatory responses and new vessel formation. They are implicated in many disease processes including atherosclerosis and cancer. IGFs play a significant role in the physiology of endothelial cells by promoting migration, tube formation and production of the vasodilator nitric oxide. These actions are mediated by the IGF1 and IGF2/mannose 6-phosphate receptors and are modulated by a family of high-affinity IGF binding proteins. IGFs also increase the number and function of endothelial progenitor cells, which may contribute to protection from atherosclerosis. IGFs promote angiogenesis, and dysregulation of the IGF system may contribute to this process in cancer and eye diseases including retinopathy of prematurity and diabetic retinopathy. In some situations, IGF deficiency appears to contribute to endothelial dysfunction, whereas IGF may be deleterious in others. These differences may be due to tissue-specific endothelial cell phenotypes or IGFs having distinct roles in different phases of vascular disease. Further studies are therefore required to delineate the therapeutic potential of IGF system modulation in pathogenic processes.

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Increased ocular levels of IGF-1 in transgenic mice lead to diabetes-like eye disease

Cited by 148 publications

References 57 publications

Alterations in alveolar epithelium differentiation and vasculogenesis in lungs of LIF/IGF‐I double deficient embryos

Alterations in alveolar epithelium differentiation and vasculogenesis in lungs of LIF/IGF‐I double deficient embryos

Long-term global retinal microvascular changes in a transgenic vascular endothelial growth factor mouse model

Endothelial cells and the IGF system

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