The development of the nervous and vascular systems constitutes primary events in the evolution of the animal kingdom; the former provides electrical stimuli and coordination, while the latter supplies oxygen and nutrients. Both systems have more in common than originally anticipated. Perhaps the most striking observation is that angiogenic factors, when deregulated, contribute to various neurological disorders, such as neurodegeneration, and might be useful for the treatment of some of these pathologies. The prototypic example of this cross-talk between nerves and vessels is the vascular endothelial growth factor or VEGF. Although originally described as a key angiogenic factor, it is now well established that VEGF also plays a crucial role in the nervous system. We describe the molecular properties of VEGF and its receptors and review the current knowledge of its different functions and therapeutic potential in the nervous system during development, health, disease and in medicine.

Role and Therapeutic Potential of VEGF in the Nervous System

OBJECTIVE Vascular endothelial growth factor (VEGF-A or VEGF) is a major pathogenic factor and therapeutic target for diabetic retinopathy (DR). Since VEGF has been proposed as a survival factor for retinal neurons, defining the cellular origin of pathogenic VEGF is necessary for the effectiveness and safety of long-term anti-VEGF therapies for DR. To determine the significance of Muller cell-derived VEGF in DR, we disrupted VEGF in Muller cells with an inducible Cre/ lox system and examined diabetes-induced retinal inflammation and vascular leakage in these conditional VEGF knockout (KO) mice. RESEARCH DESIGN AND METHODS Leukostasis was determined by counting the number of fluorescently labeled leukocytes inside retinal vasculature. Expression of biomarkers for retinal inflammation was assessed by immunoblotting of TNF-α, ICAM-1, and NF-κB. Vascular leakage was measured by immunoblotting of retinal albumin and fluorescent microscopic analysis of extravascular albumin. Diabetes-induced vascular alterations were examined by immunoblotting and immunohistochemistry for tight junctions, and by trypsin digestion assays for acellular capillaries. Retinal integrity was analyzed with morphologic and morphometric analyses. RESULTS Diabetic conditional VEGF KO mice exhibited significantly reduced leukostasis, expression of inflammatory biomarkers, depletion of tight junction proteins, numbers of acellular capillaries, and vascular leakage compared to diabetic control mice. CONCLUSIONS Muller cell-derived VEGF plays an essential and causative role in retinal inflammation, vascular lesions, and vascular leakage in DR. Therefore, Muller cells are a primary cellular target for proinflammatory signals that mediates retinal inflammation and vascular leakage in DR.

https://diabetes.diabetesjournals.org/content/diabetes/59/9/2297.full.pdf

Müller Cell-Derived VEGF Is Essential for Diabetes-Induced Retinal Inflammation and Vascular Leakage

The archetypal vascular endothelial growth factor, VEGF, arose in evolution as a signal affecting neural cells, and was subsequently co-opted to regulate vascular function. Here, the authors review the roles of the VEGF family as both aetiological factors and therapeutic targets in neurological disease.

Vascular endothelial growth factor: a neurovascular target in neurological diseases.

Muller cells are the major glia of the retina that serve numerous functions essential to retinal homeostasis, yet the contribution of Muller glial dysfunction to retinal diseases remains largely unknown. We have developed a transgenic model using a portion of the regulatory region of the retinaldehyde binding protein 1 gene for conditional Muller cell ablation and the consequences of primary Muller cell dysfunction have been studied in adult mice. We found that selective ablation of Muller cells led to photoreceptor apoptosis, vascular telangiectasis, blood–retinal barrier breakdown and, later, intraretinal neovascularization. These changes were accompanied by impaired retinal function and an imbalance between vascular endothelial growth factor-A (VEGF-A) and pigment epithelium-derived factor. Intravitreal injection of ciliary neurotrophic factor inhibited photoreceptor injury but had no effect on the vasculopathy. Conversely, inhibition of VEGF-A activity attenuated vascular leak but did not protect photoreceptors. Our findings show that Muller glial deficiency may be an important upstream cause of retinal neuronal and vascular pathologies in retinal diseases. Combined neuroprotective and anti-angiogenic therapies may be required to treat Muller cell deficiency in retinal diseases and in other parts of the CNS associated with glial dysfunction.

https://www.jneurosci.org/content/jneuro/32/45/15715.full.pdf

Conditional Müller cell ablation causes independent neuronal and vascular pathologies in a novel transgenic model

The design of materials in which assembly, mechanical response, and biological properties are controlled by protein-polysaccharide interactions may mimic the biological environment, be responsive to appropriate biological cues, and find use in many biomedical applications. Here we report the assembly of hydrogels via the noncovalent interaction of heparin-functionalized, star-PEG polymers and the therapeutically relevant, heparin-binding protein VEGF (vascular endothelial growth factor). The viscoelastic properties of these hydrogels, and the specificity of VEGF in crosslinking, were assessed via laser tweezer microrheology. The receptor-mediated delivery of VEGF, with concurrent erosion of the hydrogels, was indicated via radiometry assays of the hydrogels in the presence of VEGFR-2-modified particles, and the specificity of this interaction was indicated by a lack of erosion of the hydrogels when incubated with particles modified with a protein lacking affinity for VEGF. The VEGF delivered from the hydr...

Growth Factor Mediated Assembly of Cell Receptor-Responsive Hydrogels

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. Human VEGF165 (hVEGF165) 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. trVEGF029 mice were normoglycaemic and showed a moderate, short-term hVEGF165 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. The data suggest that even an early short-term elevation in hVEGF165 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.

/pdf/long-term-global-retinal-microvascular-changes-in-a-2j730uvivr.pdf

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

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