Intravitreal Anti-VEGF Therapy Blocks Inflammatory Cell Infiltration and Re-Entry into the Circulation in Retinal Angiogenesis

Nakao, Shintaro; Arima, Mitsuru; Ishikawa, Keijiro; Kohno, Ri-ichiro; Kawahara, Shuhei; Miyazaki, Masao; Yoshida, Shigeo; Enaida, Hiroshi; Hafezi-Moghadam, Ali; Kono, Toshihiro; Ishibashi, Tatsuro

doi:10.1167/iovs.11-9119

Cited by 60 publications

(35 citation statements)

References 23 publications

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“…On the other hand, our previous study concerning VEGF neutralizing antibody in OIR model revealed VEGF blockade could inhibit retinal angiogenesis but not avascular area. 4 ROCK inhibitors might have advantages over anti-VEGF therapy for preventing ischemia as well as the angiogenic response.…”

Section: Discussionmentioning

confidence: 99%

“…This data is contradictory to most reported data in OIR model such as VEGF inhibition. 4,30 Therefore, ROCK could play a different role in intraretinal physiological vascularization from VEGF. In fact, a recent paper using OIR model has shown that blockade of neuropilin-1 reduced both avascular area and neovascular area via ROCK inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…3 Intravitreal injections of anti-VEGF therapy was reported to inactivate retinal angiogenesis via vessel contraction and an anti-inflammatory effect. [4][5][6] However, intravitreal injections of anti-VEGF therapy have several drawbacks such as high cost, ocular pain, endophthalmitis, cardiac infarction, and cerebral stroke. 3 Furthermore, several studies have reported that anti-VEGF treatment could cause retinal ischemia and fibrovascular membrane contraction.…”

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confidence: 99%

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Vascular Normalization by ROCK Inhibitor: Therapeutic Potential of Ripasudil (K-115) Eye Drop in Retinal Angiogenesis and Hypoxia

Yamaguchi

Nakao

Arita

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. In this study, we investigated the therapeutic potential of a Rho-associated coiledcoil-containing protein kinase (ROCK) inhibitor ripasudil (K-115) eye drop on retinal neovascularization and hypoxia.METHODS. In vitro, human retinal microvascular endothelial cells (HRMECs) were pretreated with ripasudil and then stimulated with VEGF. ROCK activity was evaluated by phosphorylation of myosin phosphatase target protein (MYPT)-1. Endothelial migration and cell viability were assessed by cell migration and MTT assay, respectively. The concentration of ripasudil in the retina was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In vivo, normal saline, 0.4%, or 0.8% ripasudil were administered three times a day to mice with oxygen-induced retinopathy (OIR). The areas of neovascularization and avascular retina were also quantified with retinal flat-mounts at postnatal day (P) 15, P17, or P21. The retinal hypoxic area was evaluated using hypoxia-sensitive drug pimonidazole by immunohistochemistry at P17. The vascular normalization was also evaluated by immunohistochemistry at P17. RESULTS.Ripasudil but not fasudil significantly reduced VEGF-induced MYPT-1 phosphorylation in HRMECs at 30 lmol/L. Ripasudil significantly inhibited VEGF-induced HRMECs migration and proliferation. The concentration of ripasudil in the retina was 3.8 to 10.4 lmol/ L and 6.8 to 14.8 lmol/L after 0.4% and 0.8% ripasudil treatment, respectively. In the 0.4% and 0.8% ripasudil treated OIR mice, the areas of neovascularization as well as avascular area in the retina was significantly reduced compared with those of saline-treated mice at P17 and P21. Pimonidazole staining revealed that treatment with 0.4% and 0.8% ripasudil significantly inhibited the increase in the hypoxic area compared with saline. 0.8% ripasudil could cause intraretinal vascular sprouting and increase retinal vascular perfusion.CONCLUSIONS. Novel ROCK inhibitor ripasudil eye drop has therapeutic potential in the treatment of retinal hypoxic neovascular diseases via antiangiogenic effects as well as vascular normalization.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Vascular Normalization by ROCK Inhibitor: Therapeutic Potential of Ripasudil (K-115) Eye Drop in Retinal Angiogenesis and Hypoxia

Yamaguchi

Nakao

Arita

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…Increasing levels of a variety of inflammatory mediators, such as tumor necrosis factor (TNF)-α, VEGF, interleukin (IL)-6, IL-8, endothelin (ET)-1, and monocyte chemotactic protein (MCP)-1, have been found in the retinas or vitreous from patients with retinal NV (Yoshimura, Sonoda et al 2009). Interestingly, anti-VEGF therapy blocks inflammatory cell infiltration and re-entry into the circulation in both retinal (Nakao, Arima et al 2012) and corneal angiogenesis (Nakao, Zandi et al 2012). These findings suggest that a vicious cycle is formed by inflammatory mediators and angiogenic factors in retinal diseases.…”

Section: Er Stress and Neovascular Retinal Diseasesmentioning

confidence: 99%

The unfolded protein response in retinal vascular diseases: Implications and therapeutic potential beyond protein folding

Zhang

Jacey

Bhatta

et al. 2015

Progress in Retinal and Eye Research

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Angiogenesis is a complex, step-wise process of new vessel formation that is involved in both normal embryonic development as well as postnatal pathological processes, such as cancer, cardiovascular disease, and diabetes. Aberrant blood vessel growth, also known as neovascularization, in the retina and the choroid is a major cause of vision loss in severe eye diseases, such as diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, and central and branch retinal vein occlusion. Yet, retinal neovascularization is causally and dynamically associated with vasodegeneration, ischemia, and vascular remodeling in retinal tissues. Understanding the mechanisms of retinal neovascularization is an urgent unmet need for developing new treatments for these devastating diseases. Accumulating evidence suggests a vital role for the unfolded protein response (UPR) in regulation of angiogenesis, in part through coordinating the secretion of pro-angiogenic growth factors, such as VEGF, and modulating endothelial cell survival and activity. Herein, we summarize current research in the context of endoplasmic reticulum (ER) stress and UPR signaling in retinal angiogenesis and vascular remodeling, highlighting potential implications of targeting these stress response pathways in the prevention and treatment of retinal vascular diseases that result in visual deficits and blindness.

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“…A histologic study has shown that intravitreal anti-VEGF induces apoptosis and lessens fenestration in vascular endothelial cells, indicating that the treatment affects vascular endothelial cells (35). In another study, the intravitreal injection of anti-VEGF was shown to inhibit leukocyte trafficking in the retina, which suggests that anti-VEGF therapy could serve as a treatment for retinal inflammation (36).…”

Section: Discussionmentioning

confidence: 99%

Effects of Intravitreal Anti-VEGF Therapy on the Clinical Course of Bronchopulmonary Dysplasia

et al. 2016

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Objectives: To demonstrate the effects of the injection of intravitreal bevacizumab (IVB) on the clinical course of established bronchopulmonary dysplasia (BPD). Methods: This is a multicenter retrospective case-control study performed without any randomization or masking procedure. A total of 70 patients with BPD, including 35 cases (the IVB group) and 35 controls (the control group) were studied. Patients in the IVB group received intravitreal anti-VEGF (bevacizumab) treatment for type 1 prethreshold retinopathy of prematurity (ROP). The control group consisted of infants with BPD whose gestational age, birthweight, and gender were matched with those of the IVB group. None of the infants in the control group needed to be treated for ROP using either anti-VEGF or laser photocoagulation. Results: There was no statistically significant difference (P = 0.11) between the groups in terms of the total duration of oxygen prior to the IVB injection (65.9 ± 23.5 and 79.1 ± 33.1 days in the IVB group and control group, respectively). However, after the injection of IVB, the total duration of oxygen was significantly lower in the IVB group (mean 7 (1 -70) days vs. 16 (1 -98) days, P = 0.01). In 14 cases with mild BPD and their matched controls, the median time (25% -75%) for the discontinuation of oxygen therapy was 3 (2 -7) days and 10 (5 -15) days, respectively (P = 0.36). In 21 cases with moderate and severe BPD and their matched controls, the median time (25 -75%) for the discontinuation of oxygen therapy was 14 (7 -21) days and 22 (16 -43) days, respectively (P = 0.024). Conclusions: Intravitreal bevacizumab injection treatment for ROP cases with BPD was found to be associated with a shorter duration of oxygen use. The results of the study not only demonstrate a pathogenic correlation between ROP and BPD through an abnormal vasculogenesis, but also raise a question regarding whether or not the systemic side effects of IVB are actually adverse.

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Intravitreal Anti-VEGF Therapy Blocks Inflammatory Cell Infiltration and Re-Entry into the Circulation in Retinal Angiogenesis

Abstract: Intravitreal injection of anti-VEGF-A Ab could inhibit leukocyte trafficking in the retina, suggesting that anti-VEGF-A therapy could serve as a treatment in retinal inflammation.

Cited by 60 publications

References 23 publications

Vascular Normalization by ROCK Inhibitor: Therapeutic Potential of Ripasudil (K-115) Eye Drop in Retinal Angiogenesis and Hypoxia

Vascular Normalization by ROCK Inhibitor: Therapeutic Potential of Ripasudil (K-115) Eye Drop in Retinal Angiogenesis and Hypoxia

The unfolded protein response in retinal vascular diseases: Implications and therapeutic potential beyond protein folding

Effects of Intravitreal Anti-VEGF Therapy on the Clinical Course of Bronchopulmonary Dysplasia

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