Intravitreous Injections of Vascular Endothelial Growth Factor Produce Retinal Ischemia and Microangiopathy in an Adult Primate.

Tolentino, Michael J.; Miller, J W; Gragoudas, Evangelos S.; Flynn, Erin; Charzisrefanou, K; Ferrara, N; Adamis, A.P.

doi:10.1097/00006982-199805000-00031

Cited by 167 publications

(211 citation statements)

References 0 publications

Supporting

Mentioning

186

Contrasting

Unclassified

Order By: Relevance

“…42,43 Repeated injections of high concentrations of VEGF in eyes of nondiabetic monkeys provoke retinal changes that resemble those observed in the early stages of DR, including vascular tortuosity and microaneurysms. 44,45 Clinical trials using anti-VEGF therapies are showing promising results against advanced stages of DR. 46,47 Thus, without excluding the activation of other transduction pathways associated with retinal IPC, such as adenosine, K ATP channels, protein kinase C, 12,48 -49 and NO, 50 among others, and based on the fact that ischemia pulses abrogated the increase in VEGF, it is tempting to speculate that the induction of ischemic conditioning could behave as an anti-VEGF therapy. In fact, it was shown that injection of VEGF into healthy eyes of animals can induce diabetes-associated ocular diseases.…”

Section: Discussionmentioning

confidence: 99%

Induction of Ischemic Tolerance Protects the Retina From Diabetic Retinopathy

Fernandez

Sande

Chianelli

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

Diabetic retinopathy is a leading cause of acquired blindness. Available treatments are not very effective. We investigated the effect of a weekly application of retinal ischemia pulses (ischemic conditioning) on retinal damage induced by experimental diabetes. Diabetes was induced by an intraperitoneal injection of streptozotocin. Retinal ischemia was induced by increasing intraocular pressure to 120 mmHg for 5 minutes; this maneuver started 3 days after streptozotocin injection and was weekly repeated in one eye, whereas the contralateral eye was submitted to a sham procedure. Diabetic retinopathy was evaluated in terms of i) retinal function (electroretinogram and oscillatory potentials), ii) integrity of blood-retinal barrier (by albumin-Evans blue complex leakage and astrocyte glial fibrillary acidic protein IHC), iii) optical and electron microscopy histopathologic studies, and iv) vascular endothelial growth factor levels (using Western blot analysis and IHC). Brief ischemia pulses significantly preserved electroretinogram a-and b-wave and oscillatory potentials, avoided albumin-Evans blue leakage, prevented the decrease in astrocyte glial fibrillary acidic protein levels, reduced the appearance of retinal edemas, and prevented the increase in vascular endothelial growth factor levels induced by experimental diabetes. When the application of ischemia pulses started 6 weeks after diabetes onset, retinal function was significantly preserved. These results indicate that induction of ischemic tolerance could constitute a fertile avenue for the development of new therapeutic strategies for diabetic retinopathy treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Induction of Ischemic Tolerance Protects the Retina From Diabetic Retinopathy

Fernandez

Sande

Chianelli

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…56 VEGF is not only up-regulated in response to hypoxia and nonperfusion, but may also be an underlying cause of them. 57 In addition, VEGF can induce hypertrophy of endothelial cells of retinal capillaries, at the expense of lumen diameter. 57,58 We provide evidence for an increase in VEGF in the retinas of Atm Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

“…57 In addition, VEGF can induce hypertrophy of endothelial cells of retinal capillaries, at the expense of lumen diameter. 57,58 We provide evidence for an increase in VEGF in the retinas of Atm Ϫ/Ϫ mice. This can account for the vasoconstriction and vascular leakage that we found in the retinas of Atm Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

Raz-Prag

Galron

Segev-Amzaleg

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

Ataxia-telangiectasia is a multifaceted syndrome caused by null mutations in the ATM gene, which encodes the protein kinase ATM, a key participant in the DNA damage response. Retinal neurons are highly susceptible to DNA damage because they are terminally differentiated and have the highest metabolic activity in the central nervous system. In this study, we characterized the retina in young and aged Atmdeficient mice (Atm ؊/؊ ). At 2 months of age, angiography revealed faint retinal vasculature in Atm ؊/؊ animals relative to wild-type controls. This finding was accompanied by increased expression of vascular endothelial growth factor protein and mRNA. Fibrinogen, generally absent from wild-type retinal tissue, was evident in Atm ؊/؊ retinas, whereas mRNA of the tight junction protein occludin was significantly decreased. Immunohistochemistry labeling for occludin in 6-month-old mice showed that this decrease persists in advanced stages of the disease. Some brain disorders may have a vascular origin, 1,2 and vascular diseases can be directly linked to neuronal and synaptic dysfunction through changes in the blood flow, increase in blood-brain barrier permeability, and in nutrient supply. 3 A healthy brain relies on the proper function and communication of all cells comprising the neurovascular unit: neurons, astrocytes, brain endothelium, and vascular smooth muscle cells. 4 Impaired genomic stability interferes with cellular homeostasis and poses a constant threat to cellular viability. 5 The cell combats this threat by activating the DNA damage response (DDR), a complex signaling network that detects the DNA lesions, promotes their repair, and temporarily modulates cellular metabolism while the damage is being repaired. 6 The DDR is vigorously activated by DNA double-strand breaks (DSBs), a particularly cytotoxic DNA lesion induced by ionizing radiation, radiomimetic chemicals, and oxygen radicals. 7,8 The DNA damage response is a hierarchical process executed by sensor/mediator proteins that accumulate at DSB sites and by protein kinases that serve as transducers of the DNA damage alarm to numerous downstream effectors. 6 The primary transducer of the cellular response to DSBs is the protein kinase ATM, which phosphorylates many key players in the various branches of the DDR. 9 Ataxia-telangiectasia (A-T) is an autosomal recessive disorder caused by mutations in the ATM gene that encodes the ATM protein. 10 A-T is characterized by progressive neurodegeneration affecting mainly the cerebellum, which develops into severe neuromotor dysfunction;

show abstract

“…Vascular endothelial growth factor is crucial in the initiation and development of variable retinopathies (Aiello et al, 1994). In DR, VEGF per se is sufficient to induce vascular abnormalities including vascular leakage, microangiopathy, and neovascularization (Tolentino et al, 1996). Considering that Ang II increases VEGF and VEGF-receptor expression in retinal endothelial cells, and RAS blockade attenuates upregulation of VEGF in retinal neovascularization (Otani et al, 1998;Moravski et al, 2000), the RAS is also thought to be important in DR. Ang II acts through two types of receptors, AT1R and AT2R.…”

Section: Discussionmentioning

confidence: 99%

Blockade of Angiotensin II Attenuates VEGF-Mediated Blood—Retinal Barrier Breakdown in Diabetic Retinopathy

Kim

et al. 2008

J Cereb Blood Flow Metab

104

View full text Add to dashboard Cite

Diabetic retinopathy (DR) is the leading cause of vision loss as a major complication of diabetes mellitus. The blood-retinal barrier (BRB) breakdown is a critical early event in the pathogenesis of DR. It has been known that the rennin-angiotensin system (RAS) is important in the progression of the DR via angiotensin II (Ang II), the effector of RAS. In this study, we showed that blockade of Ang II attenuates vascular endothelial growth factor (VEGF)-mediated BRB breakdown in DR. In streptozotocin-induced diabetes, retinal vascular permeability increased with upregulation of VEGF, where Ang II and its receptors were upregulated. Ang II induced VEGF expression in retinal endothelial cells accompanied by loss of tight junction proteins. However, the blockade of Ang II by perindopril, an angiotensin converting enzyme (ACE) inhibitor, inhibited upregulation of VEGF, and prevented the loss of tight junction proteins. Moreover, inhibition of Ang II by perindopril attenuated increased vascular permeability of diabetic retina accompanied by recovery of tight junction proteins in retinal vessels. Therefore, we suggest that the RAS involves in increased vascular permeability during early stage of DR, which is mediated by VEGF. Furthermore, the ACE inhibitor may have a therapeutic potential in the treatment of diabetic BRB breakdown.

show abstract

Intravitreous Injections of Vascular Endothelial Growth Factor Produce Retinal Ischemia and Microangiopathy in an Adult Primate.

Cited by 167 publications

References 0 publications

Induction of Ischemic Tolerance Protects the Retina From Diabetic Retinopathy

Induction of Ischemic Tolerance Protects the Retina From Diabetic Retinopathy

A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

Blockade of Angiotensin II Attenuates VEGF-Mediated Blood—Retinal Barrier Breakdown in Diabetic Retinopathy

Contact Info

Product

Resources

About