VEGF-A<sub>165</sub>b Is Cytoprotective and Antiangiogenic in the Retina

Magnussen, Anette; Rennel, Emma; Hua, Jing; Bevan, Heather S.; Beazley‐Long, Nicholas; Lehrling, Christina; Gammons, Melissa V.; Floege, Juergen; Harper, Steven J.; Agostini, Hansjürgen; Bates, David O.; Churchill, Amanda J.

doi:10.1167/iovs.09-4296

Cited by 75 publications

(61 citation statements)

References 49 publications

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“…10 Such strategies will deplete both VEGF-A isoform families, thereby removing the protective actions of VEGF-A 165 b from the glomerular capillary wall and eliciting renal dysfunction and disease. Similar isoform-specific benefits of VEGF-A 165 b have also been reported in systemic sclerosis 17 and Denys-Drash syndrome, 18 ocular disease, 16,24 and cancer. 25 We show here that diabetic patients with well preserved kidney function have increased VEGF-A 165 b levels relative to VEGF-A 165 a. Transgenic podocyte-specific VEGF-A 165 b overexpression is the most analogous experimental model of this human situation, and it is noteworthy that the local upregulation of VEGF-A 165 b was the most effective approach in preventing multiple physiologic and histologic changes of diabetic nephropathy.…”

Section: Discussionsupporting

confidence: 68%

“…VEGF-A 165 b and VEGF-A 165 a bind VEGFR-2 with equal affinity but elicit different tyrosine residue phosphorylation patterns, different VEGFR-2/neuropilin-1 heterodimerization patterns, 30,31 and different downstream signaling pathways, 30 resulting in different migration, proliferation, and cytoprotection behaviors in endothelial (and other) cell types. 22,24,31 The observation that selective VEGFR-2 blockade in diabetic animals worsened albuminuria and endothelial cell apoptosis 32 is consistent with blocking beneficial endogenous VEGF-A 165 b signaling in rodents. Despite appropriate positive controls, however, the coding sequence of the rodent homolog of VEGF-A 165 b had not been identified 33,34 until very recently.…”

Section: Discussionmentioning

confidence: 82%

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Vascular Endothelial Growth Factor-A165b Is Protective and Restores Endothelial Glycocalyx in Diabetic Nephropathy

Oltean¹,

Qiu²,

Ferguson³

et al. 2015

Journal of the American Society of Nephrology

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118

166

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Diabetic nephropathy is the leading cause of ESRD in high-income countries and a growing problem across the world. Vascular endothelial growth factor-A (VEGF-A) is thought to be a critical mediator of vascular dysfunction in diabetic nephropathy, yet VEGF-A knockout and overexpression of angiogenic VEGF-A isoforms each worsen diabetic nephropathy. We examined the vasculoprotective effects of the VEGF-A isoform VEGF-A 165 b in diabetic nephropathy. Renal expression of VEGF-A 165 b mRNA was upregulated in diabetic individuals with well preserved kidney function, but not in those with progressive disease. Reproducing this VEGF-A 165 b upregulation in mouse podocytes in vivo prevented functional and histologic abnormalities in diabetic nephropathy. Biweekly systemic injections of recombinant human VEGF-A 165 b reduced features of diabetic nephropathy when initiated during early or advanced nephropathy in a model of type 1 diabetes and when initiated during early nephropathy in a model of type 2 diabetes. VEGF-A 165 b normalized glomerular permeability through phosphorylation of VEGF receptor 2 in glomerular endothelial cells, and reversed diabetes-induced damage to the glomerular endothelial glycocalyx. VEGF-A 165 b also improved the permeability function of isolated diabetic human glomeruli. These results show that VEGF-A 165 b acts via the endothelium to protect blood vessels and ameliorate diabetic nephropathy.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 82%

Vascular Endothelial Growth Factor-A165b Is Protective and Restores Endothelial Glycocalyx in Diabetic Nephropathy

Oltean¹,

Qiu²,

Ferguson³

et al. 2015

Journal of the American Society of Nephrology

Self Cite

118

166

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“…3 162 , and VEGF 165b , paradoxically a variant reported to have an inhibitory effect on VEGF-induced angiogenesis (9). This isoform inhibits neovascularization but not revascularization, and is cytoprotective for endothelial and epithelial cells in vivo and in vitro.…”

Section: Vegf: General Actions Isoforms and Receptorsmentioning

confidence: 99%

Ocular Anti-VEGF Therapy for Diabetic Retinopathy: The Role of VEGF in the Pathogenesis of Diabetic Retinopathy

2014

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Diabetic retinopathy is the leading cause of visual impairment and preventable blindness, and represents a significant socioeconomic cost for health care systems worldwide. Therefore, new approaches beyond current standards of diabetes care are needed. Based on the crucial pathogenic role of vascular endothelial growth factor (VEGF) in the development of diabetic macular edema (DME), intravitreal anti-VEGF agents have emerged as new treatments. To provide an understanding of the rationale for use and clinical efficacy of anti-VEGF treatment, we examine this topic in a two-part Bench to Clinic narrative. In the Bench narrative, we provide an overview of the role of VEGF in the pathogenesis of diabetic retinopathy, the molecular characteristics of anti-VEGF agents currently used, and future perspectives and challenges in this area. In the Clinic narrative that follows our contribution, Cheung et al. provide an overview of the current evidence from clinical trials on anti-VEGF therapy for diabetic retinopathy.

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“…VEGF may have different effects in different cell types depending on different splice variants [233]. The endogenous splice isoform VEGF-A 165 b has shown a potent neuroprotective effect in hippocampal and cerebro-cortical neurons (mediated by VEGFR2 and neuropilin-1 co-stimulation) with no propermeability property [78,234]. This isoform may be an interesting add-on therapy option against axon damage in progressive MS, with fewer adverse vascular effects.…”

Section: Therapeutic Potential Of Targeting Angiogenesismentioning

confidence: 99%

Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis

Girolamo

Coppola

Ribatti

et al. 2014

Acta Neuropathologica Communications

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Angiogenesis, the formation of new vessels, is found in Multiple Sclerosis (MS) demyelinating lesions following Vascular Endothelial Growth Factor (VEGF) release and the production of several other angiogenic molecules. The increased energy demand of inflammatory cuffs and damaged neural cells explains the strong angiogenic response in plaques and surrounding white matter. An angiogenic response has also been documented in an experimental model of MS, experimental allergic encephalomyelitis (EAE), where blood-brain barrier disruption and vascular remodelling appeared in a pre-symptomatic disease phase. In both MS and EAE, VEGF acts as a pro-inflammatory factor in the early phase but its reduced responsivity in the late phase can disrupt neuroregenerative attempts, since VEGF naturally enhances neuron resistance to injury and regulates neural progenitor proliferation, migration, differentiation and oligodendrocyte precursor cell (OPC) survival and migration to demyelinated lesions. Angiogenesis, neurogenesis and oligodendroglia maturation are closely intertwined in the neurovascular niches of the subventricular zone, one of the preferential locations of inflammatory lesions in MS, and in all the other temporary vascular niches where the mutual fostering of angiogenesis and OPC maturation occurs. Angiogenesis, induced either by CNS inflammation or by hypoxic stimuli related to neurovascular uncoupling, appears to be ineffective in chronic MS due to a counterbalancing effect of vasoconstrictive mechanisms determined by the reduced axonal activity, astrocyte dysfunction, microglia secretion of free radical species and mitochondrial abnormalities. Thus, angiogenesis, that supplies several trophic factors, should be promoted in therapeutic neuroregeneration efforts to combat the progressive, degenerative phase of MS.

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VEGF-A₁₆₅b Is Cytoprotective and Antiangiogenic in the Retina

Abstract: The survival effects of VEGF-A(165)b signaling can protect the retina from ischemic damage. These results suggest that VEGF-A(165)b may be a useful therapeutic agent in ischemia-induced angiogenesis and a cytoprotective agent for retinal pigment epithelial cells.

Cited by 75 publications

References 49 publications

Vascular Endothelial Growth Factor-A165b Is Protective and Restores Endothelial Glycocalyx in Diabetic Nephropathy

Vascular Endothelial Growth Factor-A165b Is Protective and Restores Endothelial Glycocalyx in Diabetic Nephropathy

Ocular Anti-VEGF Therapy for Diabetic Retinopathy: The Role of VEGF in the Pathogenesis of Diabetic Retinopathy

Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis

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VEGF-A165b Is Cytoprotective and Antiangiogenic in the Retina

Abstract: The survival effects of VEGF-A(165)b signaling can protect the retina from ischemic damage. These results suggest that VEGF-A(165)b may be a useful therapeutic agent in ischemia-induced angiogenesis and a cytoprotective agent for retinal pigment epithelial cells.

Cited by 75 publications

References 49 publications

Vascular Endothelial Growth Factor-A165b Is Protective and Restores Endothelial Glycocalyx in Diabetic Nephropathy

Vascular Endothelial Growth Factor-A165b Is Protective and Restores Endothelial Glycocalyx in Diabetic Nephropathy

Ocular Anti-VEGF Therapy for Diabetic Retinopathy: The Role of VEGF in the Pathogenesis of Diabetic Retinopathy

Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis

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Product

Resources

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VEGF-A₁₆₅b Is Cytoprotective and Antiangiogenic in the Retina