Alterations of Retinal Vasculature in Cystathionine-Beta-Synthase Mutant Mice, a Model of Hyperhomocysteinemia

Tawfik, Amany; Al‐Shabrawey, Mohamed; Roon, Penny; Sonne, Srinivas; Covar, Jason; Matragoon, Surapoon; Ganapathy, Preethi S.; Atherton, Sally S.; El-Remessy, Azza B.; Ganapathy, Vadivel; Smith, Sylvia B.

doi:10.1167/iovs.12-10536

Cited by 41 publications

(49 citation statements)

References 35 publications

(55 reference statements)

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“…In this study, we used the FAL model by employing a genetically engineered mouse model (CBS +/À ) mimicking HHcy conditions as seen in HHcy patients for the purpose of studying the postischemic neoangiogenesis phenomenon during HHcy. Our results add to the growing body of evidence that HHcy is associated with defective neoangiogenesis as shown in other in vivo experiments (Tan et al 2006;Tawfik et al 2013). Earlier, studies also showed that high Hcy (HHcy) has a profound inhibitory effect on EC proliferation and their migration (Cai et al 2007;Li et al 2006;Ozsvari et al 2010;Papapetropoulos et al 2009;Tan et al 2006).…”

Section: Discussionsupporting

confidence: 79%

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Hydrogen sulfide improves postischemic neoangiogenesis in the hind limb of cystathionine-β-synthase mutant mice via PPAR-γ/VEGF axis

et al. 2018

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Neoangiogenesis is a fundamental process which helps to meet energy requirements, tissue growth, and wound healing. Although previous studies showed that Peroxisome proliferator‐activated receptor (PPAR‐γ) regulates neoangiogenesis via upregulation of vascular endothelial growth factor (VEGF), and both VEGF and PPAR‐γ expressions were inhibited during hyperhomocysteinemic (HHcy), whether these two processes could trigger pathological effects in skeletal muscle via compromising neoangiogenesis has not been studied yet. Unfortunately, there are no treatment options available to date for ameliorating HHcy‐mediated neoangiogenic defects. Hydrogen sulfide (H2S) is a novel gasotransmitter that can induce PPAR‐γ levels. However, patients with cystathionine‐β‐synthase (CBS) mutation(s) cannot produce a sufficient amount of H2S. We hypothesized that exogenous supplementation of H2S might improve HHcy‐mediated poor neoangiogenesis via the PPAR‐γ/VEGF axis. To examine this, we created a hind limb femoral artery ligation (FAL) in CBS +/− mouse model and treated them with GYY4137 (a long‐acting H2S donor compound) for 21 days. To evaluate neoangiogenesis, we used barium sulfate angiography and laser Doppler blood flow measurements in the ischemic hind limbs of experimental mice post‐FAL to assess blood flow. Proteins and mRNAs levels were studied by Western blots and qPCR analyses. HIF1‐α, VEGF, PPAR‐γ and p‐eNOS expressions were attenuated in skeletal muscle of CBS +/− mice after 21 days of FAL in comparison to wild‐type (WT) mice, that were improved via GYY4137 treatment. We also found that the collateral vessel density and blood flow were significantly reduced in post‐FAL CBS +/− mice compared to WT mice and these effects were ameliorated by GYY4137. Moreover, we found that plasma nitrite levels were decreased in post‐FAL CBS +/− mice compared to WT mice, which were mitigated by GYY4137 supplementation. These results suggest that HHcy can inhibit neoangiogenesis via antagonizing the angiogenic signal pathways encompassing PPAR‐γ/VEGF axis and that GYY4137 could serve as a potential therapeutic to alleviate the harmful metabolic effects of HHcy conditions.

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Section: Discussionsupporting

confidence: 79%

“…; Tawfik et al. ). Earlier, studies also showed that high Hcy (HHcy) has a profound inhibitory effect on EC proliferation and their migration (Cai et al.…”

Section: Discussionmentioning

confidence: 98%

Hydrogen sulfide improves postischemic neoangiogenesis in the hind limb of cystathionine-β-synthase mutant mice via PPAR-γ/VEGF axis

et al. 2018

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“…Three-week-old Cbs −/− mice have a seven-fold elevation of tHcy in the retina and have distinct alterations in retinal architecture and abnormal electroretinograms [59, 60]. Follow-up studies indicated that there was vascular leakage in the retina as determined by angiography [61]. More recently, it has been shown that Cbs −/− mice have altered retinal pigment epithelial structure [62].…”

Section: Eye Phenotypesmentioning

confidence: 99%

Cystathionine β-synthase deficiency: Of mice and men

Kruger

2017

Molecular Genetics and Metabolism

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Cystathionine β-synthase (CBS) deficiency (Online Mendelian Inheritance in Man [OMIM] 236200) is an autosomal recessive disorder that is caused by mutations in the CBS gene. It is the most common inborn error of sulfur metabolism and is the cause of classical homocystinuria, a condition characterized by very high levels of plasma total homocysteine and methionine. Although recognized as an inborn error of metabolism over 60 years ago, these is still much we do not understand related to how this specific metabolic defect gives rise to its distinct phenotypes. To try and answer these questions, several groups have developed mouse models on CBS deficiency. In this article, we will review various mouse models of CBS deficiency and discuss how these mouse models compare to human CBS deficient patients.

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“…VEGF, a potent mediator of vascular permeability in the retina is also implicated in retinal neovascularization in ischemic retinopathies (76)(77)(78)(79)(80)(81). The aqueous levels ofVEGF and IL-6 are correlated significantly with the severity of macular edema.…”

mentioning

confidence: 99%

Vascular Endothelial Growth Factor (VEGF), Mast Cells and Inflammation

Shaik‐Dasthagirisaheb

Varvara

Murmura

et al. 2013

Int J Immunopathol Pharmacol

115

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Vascular endothelial growth factor (VEGF) is one of the most important inducers of angiogenesis, therefore blocking angiogenesis has led to great promise in the treatment of various cancers and inflammatory diseases. VEGF, expressed in response to soluble mediators such as cytokines and growth factors, is important in the physiological development of blood vessels as well as development of vessels in tumors. In cancer patients VEGF levels are increased, and the expression of VEGF is associated with poor prognosis in diseases. VEGF is a mediator of angiogenesis and inflammation which are closely integrated processes in a number of physiological and pathological conditions including obesity, psoriasis, autoimmune diseases and tumor. Mast cells can be activated by anti-IgE to release potent mediators of inflammation and can also respond to bacterial or viral antigens, cytokines, growth factors and hormones, leading to differential release of distinct mediators without degranulation. Substance P strongly induces VEGF in mast cells, and IL-33 contributes to the stimulation and release of VEGF in human mast cells in a dose-dependent manner and acts synergistically in combination with Substance P. Here we report a strong link between VEGF and mast cells and we depict their role in inflammation and immunity.

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Alterations of Retinal Vasculature in Cystathionine-Beta-Synthase Mutant Mice, a Model of Hyperhomocysteinemia

Cited by 41 publications

References 35 publications

Hydrogen sulfide improves postischemic neoangiogenesis in the hind limb of cystathionine-β-synthase mutant mice via PPAR-γ/VEGF axis

Hydrogen sulfide improves postischemic neoangiogenesis in the hind limb of cystathionine-β-synthase mutant mice via PPAR-γ/VEGF axis

Cystathionine β-synthase deficiency: Of mice and men

Vascular Endothelial Growth Factor (VEGF), Mast Cells and Inflammation

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