Neurofibromin is a novel regulator of Ras-induced reactive oxygen species production in mice and humans

Bessler, Waylan; Hudson, Farlyn Z.; Zhang, Hanfang; Harris, Valerie; Wang, Yusi; Mund, Julie A.; Downing, Brandon D.; Ingram, David A.; Case, Jamie; Fulton, David; Stansfield, Brian K.

doi:10.1016/j.freeradbiomed.2016.06.002

Cited by 22 publications

(20 citation statements)

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“… 50 This line of thinking is intriguing because we recently demonstrated that neurofibromin is a master regulator of macrophage differentiation and neurofibromin-deficient macrophages exhibit a prosurvival phenotype characterized by enhanced proliferation, migration, adhesion, and secretion of growth factors and reactive oxygen species. 51 – 54 Further, the similarities/differences in neovascular tuft formation between Nf1 +/− and Nf1 flox/+ ;Tie2cre retinas in response to hyperoxia/hypoxia may be explained by the presence of the Tie2 promoter in both EC and macrophages. 55 – 57 Deletion of Nf1 in macrophages increases ROS production and growth factor secretion, which may lead to excessive proliferation of neurofibromin-deficient retinal EC.…”

Section: Discussionmentioning

confidence: 99%

“… 55 – 57 Deletion of Nf1 in macrophages increases ROS production and growth factor secretion, which may lead to excessive proliferation of neurofibromin-deficient retinal EC. 52 , 53 Thus, the neovascular phenotype observed in Nf1 +/− and Nf1 flox/+ ;Tie2cre retinas may be explained by a cooperation between infiltrating neurofibromin-deficient macrophages and/or resident microglia and angiogenic EC to promote pathologic angiogenesis at the expense of retinal revascularization. Based on the overlapping expression of Tie2 in both EC and hematopoietic cells, we intercrossed the Nf1 flox/flox mice with mice expressing Cre under the VE cadherin promoter (VECre).…”

Section: Discussionmentioning

confidence: 99%

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Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization

Zhang

Hudson

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PurposeNeurofibromatosis type 1 (NF1) is the result of inherited mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. Eye manifestations are common in NF1 with recent reports describing a vascular dysplasia in the retina and choroid. Common features of NF1 retinopathy include tortuous and dilated feeder vessels that terminate in capillary tufts, increased endothelial permeability, and neovascularization. Given the retinal vascular phenotype observed in persons with NF1, we hypothesize that preserving neurofibromin may be a novel strategy to control pathologic retinal neovascularization.MethodsNf1 expression in human endothelial cells (EC) was reduced using small hairpin (sh) RNA and EC proliferation, migration, and capacity to form vessel-like networks were assessed in response to VEGF and hypoxia. Wild-type (WT), Nf1 heterozygous (Nf1+/−), and Nf1flox/+;Tie2cre pups were subjected to hyperoxia/hypoxia using the oxygen-induced retinopathy model. Retinas were analyzed quantitatively for extent of retinal vessel dropout, neovascularization, and capillary branching.ResultsNeurofibromin expression was suppressed in response to VEGF, which corresponded with activation of Mek-Erk and PI3-K-Akt signaling. Neurofibromin-deficient EC exhibited enhanced proliferation and network formation in response to VEGF and hypoxia via an Akt-dependent mechanism. In response to hyperoxia/hypoxia, Nf1+/− retinas exhibited increased vessel dropout and neovascularization when compared with WT retinas. Neovascularization was similar between Nf1+/− and Nf1flox/+;Tie2cre retinas, but capillary drop out in Nf1flox/+;Tie2cre retinas was significantly reduced when compared with Nf1+/− retinas.ConclusionsThese data suggest that neurofibromin expression is essential for controlling endothelial cell proliferation and retinal neovascularization and therapies targeting neurofibromin-deficient EC may be beneficial.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization

Zhang

Hudson

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…It has also been shown that systemic vascular smooth muscle cells have an abnormal proliferative phenotype in case of loss of NF1, depending on ERK pathway [59]. In addition, another study showed that there is an increase in reactive oxygen species production in NF1 that could participate in the development of a systemic vasculopathy [60]. However, these mechanisms have not been studied on pulmonary vascular cells.…”

Section: Pathophysiology Of Ph In Nf1mentioning

confidence: 99%

Pulmonary hypertension associated with neurofibromatosis type 1

et al. 2018

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Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is a frequent autosomal dominant genetic disorder with a prevalence of 1 in 3000. Pulmonary hypertension (PH) associated with NF1 (PH-NF1) is a rare but severe complication of NF1 and is classified as Group 5 PH, defined as "PH with unclear and/or multifactorial mechanisms". A literature review in PubMed on the association between NF1 and PH identified 18 articles describing 31 cases. PH-NF1 was characterised by a female predominance, an advanced age at diagnosis, an association with parenchymal lung disease in two out of three cases and poor long-term prognosis. NF1 is generally associated with interstitial lung disease but some cases of severe PH without parenchymal lung disease suggest that there could be a specific pulmonary vascular disease. There is no data available on the efficacy of specific pulmonary arterial hypertension treatment in PH-NF1. Therefore, these patients should be evaluated in expert PH centres and referred for lung transplantation at an early stage. As these patients have an increased risk of malignancy, careful assessment of the post-transplant malignancy risk prior to listing for transplantation is necessary. Clinical trials are needed to evaluate promising treatments targeting the RAS-downstream signalling pathways.

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“…Partial or complete loss of the NF1 gene results in increased PKCδ-mediated p47phox phosphorylation through the activation of p21(Ras), resulting in increased NADPH oxidase 2 activity, alterations in the redox balance and pro-inflammatory effects 32 – 34 . Acceleration of Ras activity also has an impact on multiple kinases of its downstream signaling pathways, including Erk and Akt, both of which are involved in the modulation of the phenotype of cells making up the vascular wall in NF1 heterozygous (Nf1 +/− ) animal model 35 , 36 . Nf1 +/− mutant mice develop a thick neointima, resembling human arterial disease.…”

Section: Discussionmentioning

confidence: 99%

Functional and morphological cardiovascular alterations associated with neurofibromatosis 1

Cutruzzolà

Irace

Frazzetto

et al. 2020

Sci Rep

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Subjects with Neurofibromatosis 1 (NF1) develop vascular complications. The protein product of the gene affected in NF1, neurofibromin, physiologically modulates endothelial function and preserves vascular and myocardial structure. Our study aimed to verify whether subjects with NF1 have early, preclinical abnormalities of carotid artery structure, brachial artery function, and cardiac function. We recruited 22 NF1 subjects without previous cardiovascular events and 22 healthy control subjects. All subjects underwent measurement of carotid artery intima-media thickness (IMT), evaluation of brachial artery endothelial function after ischemia and exercise, and cardiac function. Mean IMT was 543 ± 115 μ in NF1 subjects and 487 ± 70 μ in Controls (p < 0.01). Endothelial function was significantly dumped in NF1 subjects. The dilation after ischemia and exercise was respectively 7.5(± 4.8)% and 6.7(± 3.0)% in NF1 versus 10.5(± 1.2)% and 10.5(± 2.1)% in control subjects (p < 0.02; p < 0.002). Left ventricular systolic function assessed by Global Longitudinal Strain was significantly different between NF1 subjects and Controls: − 19.3(± 1.7)% versus − 21.5(± 2.7)% (p < 0.008). These findings demonstrate that NF1 patients have early morphological and functional abnormalities of peripheral arteries and systolic cardiac impairment and suggest the need for a tight cardiovascular risk evaluation and primary prevention in subjects with NF1. Neurofibromatosis 1 (NF1) is a common genetic disease, affecting approximately 1 in 3,500 subjects. It has an autosomal dominant inheritance with complete penetrance, variable expression, and a high rate of new mutations. The disease is characterized by cafe-au-lait spots, dermal neurofibromas, skeletal dysplasia, Lish nodules, and optic glioma 1. Neurofibromin (encoded by the NF1 gene) is a modulator of cell growth, downregulates ras signaling, and its loss of function promotes cellular proliferation 2. For these reasons, subjects with NF1 have increased risk for malignancies like peripheral nerve sheath tumor, leukemia, and rhabdomyosarcoma. Furthermore, they may develop vascular complications as renal artery stenosis with secondary hypertension, aneurysm, arterial stenosis/occlusion, myocardial infarction, and cerebral or visceral infarcts arteriovenous fistulae 3. The vascular involvement does not seem directly linked to the proliferation and malignant transformation of neural-crest derivatives 2. Though pathogenesis of vascular lesions in NF1 remains unclear, previous studies in murine models and humans demonstrated that neurofibromin is expressed in the endothelial cells and vascular smooth muscle cells as well 2,4. Therefore NF1 vasculopathy might be the consequence of a direct involvement in vascular layers 5. Cardiac alterations have also been under the spotlight in NF1. The neurofibromin protein is physiologically involved in cardiac development 6. Besides, microdeletions of the NF1 gene often involve the nearby SUZ12 and CENTA2 genes, whose haploinsufficiency may also influence c...

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Neurofibromin is a novel regulator of Ras-induced reactive oxygen species production in mice and humans

Cited by 22 publications

References 77 publications

Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization

Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization

Pulmonary hypertension associated with neurofibromatosis type 1

Functional and morphological cardiovascular alterations associated with neurofibromatosis 1

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