Role of TGF-β in proliferative vitreoretinal diseases and ROCK as a therapeutic target

Kita, Takeshi; Hata, Yoshinobu; Arita, Ryoichi; Kawahara, Shuhei; Matsuda, Masayoshi; Nakao, Shintaro; Mochizuki, Yasutaka; Enaida, Hiroshi; Goto, Yoshinobu; Shimokawa, Hiroaki; Hafezi-Moghadam, Ali; Ishibashi, Tatsuro

doi:10.1073/pnas.0804054105

Cited by 182 publications

(136 citation statements)

References 37 publications

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“…Our recent experiments have confirmed that repeated intravitreal injections of fasudil at a final concentration of 30 mol/l in rabbit eyes and single intravitreal injection of fasudil up to 100 mol/l in rat eyes did not cause apparent electrophysiological or morphological changes in retinal tissues or induction of inflammatory cells, compared with the untreated control eyes (36). Intravitreal injection of vehicle also did not cause significant leukocyte adhesion or endothelial damage in rat retinas, compared with untreated control.…”

Section: Discussionsupporting

confidence: 61%

Rho Kinase Inhibition by Fasudil Ameliorates Diabetes-Induced Microvascular Damage

et al. 2009

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OBJECTIVE-Leukocyte adhesion in retinal microvasuculature substantially contributes to diabetic retinopathy. Involvement of the Rho/Rho kinase (ROCK) pathway in diabetic microvasculopathy and therapeutic potential of fasudil, a selective ROCK inhibitor, are investigated. RESEARCH DESIGN AND METHODS-Localization ofRhoA/ROCK and Rho activity were examined in retinal tissues of rats. Impact of intravitreal fasudil administration on retinal endothelial nitric oxide synthase (eNOS) and myosin phosphatase target protein (MYPT)-1 phosphorylation, intercellular adhesion molecule-1 (ICAM-1) expression, leukocyte adhesion, and endothelial damage in rat eyes were investigated. Adhesion of neutrophils from diabetic retinopathy patients or nondiabetic control subjects to cultured microvascular endothelial cells was quantified. The potential of fasudil for endothelial protection was investigated by measuring the number of adherent neutrophils and terminal transferase-mediated dUTP nick-end labeling-positive endothelial cells.RESULTS-RhoA and ROCK colocalized predominantly in retinal microvessels. Significant Rho activation was observed in retinas of diabetic rats. Intravitreal fasudil significantly increased eNOS phosphorylation, whereas it reduced MYPT-1 phosphorylation, ICAM-1 expression, leukocyte adhesion, and the number of damaged endothelium in retinas of diabetic rats. Neutrophils from diabetic retinopathy patients showed significantly higher adhesion to cultured endothelium and caused endothelial apoptosis, which was significantly reduced by fasudil. Blockade of the Fas-FasL interaction prevented endothelial apoptosis. The protective effect of fasudil on endothelial apoptosis was significantly reversed by N-nitro-L-arginine methyl ester, a NOS inhibitor, whereas neutrophil adhesion remained unaffected. CONCLUSIONS-The

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Section: Discussionsupporting

confidence: 61%

Rho Kinase Inhibition by Fasudil Ameliorates Diabetes-Induced Microvascular Damage

et al. 2009

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“…of TGF-β signaling (26,27). Strikingly, p-MLC was significantly decreased (despite increased MLC expression) early after TβRII knockdown, and it persisted long-term ( Figure 4, C and D, and Supplemental Figure 9B).…”

Section: Figurementioning

confidence: 85%

Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis

et al. 2014

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TGF-β is essential for vascular development; however, excess TGF-β signaling promotes thoracic aortic aneurysm and dissection in multiple disorders, including Marfan syndrome. Since the pathology of TGF-β overactivity manifests primarily within the arterial media, it is widely assumed that suppression of TGF-β signaling in vascular smooth muscle cells will ameliorate aortic disease. We tested this hypothesis by conditional inactivation of Tgfbr2, which encodes the TGF-β type II receptor, in smooth muscle cells of postweanling mice. Surprisingly, the thoracic aorta rapidly thickened, dilated, and dissected in these animals. Tgfbr2 disruption predictably decreased canonical Smad signaling, but unexpectedly increased MAPK signaling. Type II receptor-independent effects of TGF-β and pathological responses by nonrecombined smooth muscle cells were excluded by serologic neutralization. Aortic disease was caused by a perturbed contractile apparatus in medial cells and growth factor production by adventitial cells, both of which resulted in maladaptive paracrine interactions between the vessel wall compartments. Treatment with rapamycin restored a quiescent smooth muscle phenotype and prevented dissection. Tgfbr2 disruption in smooth muscle cells also accelerated aneurysm growth in a murine model of Marfan syndrome. Our data indicate that basal TGF-β signaling in smooth muscle promotes postnatal aortic wall homeostasis and impedes disease progression.

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“…[8][9][10] Furthermore, TGF-b mediates contraction of preretinal membranes. 11 TGF-b is induced in the vitreous in proliferative diabetic retinopathy and proliferative vitreoretinopathy. [12][13][14] Matrix metalloproteinases (MMPs) are calcium-or zinc-dependent extracellular proteolytic enzymes that have a role in degrading and remodelling of extracellular matrix in various physiological and pathological conditions including ischemic vitreoretinal eye diseases.…”

Section: Introductionmentioning

confidence: 99%

High intravitreal TGF-β1 and MMP-9 levels in eyes with retinal vein occlusion

Tuuminen

Loukovaara

2014

Eye

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Purpose Vascular endothelial growth factor is a leading target to reduce macular oedema and improve visual acuity in patients with retinal vein occlusion (RVO), whereas the role of vascular destabilizing and fibroproliferative transforming growth factor (TGF)-b1 and matrix metalloproteinases (MMP)-2 and -9 in pathological manifestations of RVO is anticipated but less studied. Methods Undiluted vitreous samples were collected from three central RVO and one branch RVO eyes, all with neovascularization and fibrosis-related sight-threatening complications of RVO. Undiluted vitreous samples of 40 eyes operated due to nonischemic condition either macular hole or pucker were used as controls. Growth factor and protease concentrations were measured by ELISA and gelatin zymography. Results Vitreous concentrations of TGF-b1 (92.0 ± 17.4 pg/ml vs 18.3 ± 27.0 pg/ml, mean ± SD; P ¼ 0.002) and MMP-9 (847.9 ± 1196.4 AU/ml vs 87.7 ± 174.0 AU/ml; P ¼ 0.010) were higher in the eyes with ischemic RVO than in the controls. Conclusions High intravitreal levels of TGF-b1 and MMP-9 are found in RVO eyes having neovascular and fibrosis manifestation. Further studies are warranted to elucidate whether targeting TGF-b1 and MMP-9 could be beneficial in patients with ischemic RVO.

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Role of TGF-β in proliferative vitreoretinal diseases and ROCK as a therapeutic target

Cited by 182 publications

References 37 publications

Rho Kinase Inhibition by Fasudil Ameliorates Diabetes-Induced Microvascular Damage

Rho Kinase Inhibition by Fasudil Ameliorates Diabetes-Induced Microvascular Damage

Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis

High intravitreal TGF-β1 and MMP-9 levels in eyes with retinal vein occlusion

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