Diabetic retinopathy is associated with a switch in splicing from anti- to pro-angiogenic isoforms of vascular endothelial growth factor

Perrin, RM; Konopatskaya, Olga; Qiu, Yan; Harper, Steven J.; Bates, David O.; Churchill, AJ

doi:10.1007/s00125-005-1951-8

Cited by 189 publications

(192 citation statements)

References 15 publications

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“…165 is a potent inducer of retinal vascular inflammation as well as a mediator of neuronal survival, whereas VEGF 121 promotes neuronal survival, but does not induce vascular inflammation (Ishida et al, 2003;Nishijima et al, 2007). Decreased levels of the dominant negative splice variant VEGF 165b were found in vitreous samples from patients with diabetic retinopathy, suggesting that a molecular switch between the VEGF 165 and VEGF 165b could be involved the development of diabetic retinopathy (Perrin et al, 2005). More study is needed to define the specific molecular events that regulate VEGF mRNA splicing and to see how this process is altered in the diabetic retina.…”

Section: Post-transcriptional Regulation Of Vegf Expression-mentioning

confidence: 99%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

598

523

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Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.

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Section: Post-transcriptional Regulation Of Vegf Expression-mentioning

confidence: 99%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

598

523

View full text Add to dashboard Cite

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“…This antibody has previously been shown to detect both VEGF xxx b and VEGF xxx isoforms, and both heparin-binding and nonheparin-binding isoforms (Woolard et al, 2004;Perrin et al, 2005). Serial sections (6 mm) were cut from tissue blocks of excised melanoma from the melanoma archive at Frenchay Hospital, Bristol.…”

Section: -Test)mentioning

confidence: 99%

“…The mRNA encoding this isoform, termed VEGF 165 b (Bates et al, 2002; Figure 1), was demonstrated in renal cortical tissue, and almost all other normal tissues examined. Subsequent work has identified other isoforms using this distal splice site (DSS), including VEGF 121 b, VEGF 189 b and VEGF 145 b in normal human tissues (Woolard et al, 2004;Perrin et al, 2005). This alternative family of isoforms is termed the VEGF xxx b family, in contrast with the VEGF xxx family where xxx denotes the aminoacid number (Perrin et al, 2005).…”

mentioning

confidence: 99%

“…Subsequent work has identified other isoforms using this distal splice site (DSS), including VEGF 121 b, VEGF 189 b and VEGF 145 b in normal human tissues (Woolard et al, 2004;Perrin et al, 2005). This alternative family of isoforms is termed the VEGF xxx b family, in contrast with the VEGF xxx family where xxx denotes the aminoacid number (Perrin et al, 2005). Expression of VEGF 165 b mRNA was downregulated in renal cell carcinoma (Bates et al, 2002), prostate cancer (Woolard et al, 2004) and the vitreous of patients with diabetic retinopathy (Perrin et al, 2005), all angiogenic conditions.…”

mentioning

confidence: 99%

“…This alternative family of isoforms is termed the VEGF xxx b family, in contrast with the VEGF xxx family where xxx denotes the aminoacid number (Perrin et al, 2005). Expression of VEGF 165 b mRNA was downregulated in renal cell carcinoma (Bates et al, 2002), prostate cancer (Woolard et al, 2004) and the vitreous of patients with diabetic retinopathy (Perrin et al, 2005), all angiogenic conditions. Subsequently, VEGF 165 b protein was shown to significantly and dose dependently inhibit VEGF 165 -mediated proliferation and migration of endothelial cells, vasodilatation of mesenteric arteries and angiogenesis in two different models of VEGF 165 -driven blood vessel growth (Woolard et al, 2004).…”

mentioning

confidence: 99%

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Expression of VEGFxxxb, the inhibitory isoforms of VEGF, in malignant melanoma

et al. 2007

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Malignant melanoma is the most lethal of the skin cancers and the UK incidence is rising faster than that of any other cancer. Angiogenesis -the growth of new vessels from preexisting vasculature -is an absolute requirement for tumour survival and progression beyond a few hundred microns in diameter. We previously described a class of anti-angiogenic isoforms of VEGF, VEGF xxx b, that inhibit tumour growth in animal models, and are downregulated in some cancers, but have not been investigated in melanoma. To determine whether VEGF xxx b expression was altered in melanoma, PCR and immunohistochemistry of archived human tumour samples were used. In normal epidermis and in a proportion of melanoma samples, VEGF xxx b staining was seen. Some melanomas had much weaker staining. Subsequent examination revealed that expression was significantly reduced in primary melanoma samples (both horizontal and vertical growth phases) from patients who subsequently developed tumour metastasis compared with those who did not (analysis of variance (ANOVA) Po0.001 metastatic vs nonmetastatic), irrespective of tumour thickness, while the surrounding epidermis showed no difference in expression. Staining for total VEGF expression showed staining in metastatic and nonmetastatic melanomas, and normal epidermis. An absence of VEGF xxx b expression appears to predict metastatic spread in patients with primary melanoma. These results suggest that there is a switch in splicing as part of the metastatic process, from anti-angiogenic to pro-angiogenic VEGF isoforms. This may form part of a wider metastatic splicing phenotype.

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Functions of SRPK, CLK and DYRK kinases in stem cells, development, and human developmental disorders

Hogg,

Findlay

2023

FEBS Letters

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Human developmental disorders encompass a wide range of debilitating physical conditions and intellectual disabilities. Perturbation of protein kinase signalling underlies the development of some of these disorders. For example, disrupted SRPK signalling is associated with intellectual disabilities, and the gene dosage of DYRKs can dictate the pathology of disorders including Down's syndrome. Here, we review the emerging roles of the CMGC kinase families SRPK, CLK, DYRK, and sub‐family HIPK during embryonic development and in developmental disorders. In particular, SRPK, CLK, and DYRK kinase families have key roles in developmental signalling and stem cell regulation, and can co‐ordinate neuronal development and function. Genetic studies in model organisms reveal critical phenotypes including embryonic lethality, sterility, musculoskeletal errors, and most notably, altered neurological behaviours arising from defects of the neuroectoderm and altered neuronal signalling. Further unpicking the mechanisms of specific kinases using human stem cell models of neuronal differentiation and function will improve our understanding of human developmental disorders and may provide avenues for therapeutic strategies.

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Diabetic retinopathy is associated with a switch in splicing from anti- to pro-angiogenic isoforms of vascular endothelial growth factor

Abstract: Aims/hypothesis: Proliferative diabetic retinopathy results from excess blood vessel growth into the vit-

Cited by 189 publications

References 15 publications

Vascular endothelial growth factor in eye disease

Vascular endothelial growth factor in eye disease

Expression of VEGFxxxb, the inhibitory isoforms of VEGF, in malignant melanoma

Functions of SRPK, CLK and DYRK kinases in stem cells, development, and human developmental disorders

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