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Intravitreally Injected Anti-VEGF Antibody Reduces Brown Fat in Neonatal Mice.

Jo DH, Park SW, Cho CS, Powner MB, Kim JH, Fruttiger M, Kim JH - PLoS ONE (2015)

Bottom Line: Furthermore, in interscapular brown adipose tissue, we found lipid droplet accumulation, decreased VEGF levels, loss of vascular network, and decreased expression of mitochondria-related genes, Ppargc1a and Ucp1, all of which are characteristics of "whitening" of brown fat.With increasing age and body weight, brown fat restored its morphology and vascularity.We suggest that more attention should be focused on the metabolic and developmental significance of brown adipose tissue in bevacizumab treated retinopathy of prematurity infants.

View Article: PubMed Central - PubMed

Affiliation: Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea; Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea.

ABSTRACT
Anti-vascular endothelial growth factor (VEGF) agents are the mainstay treatment for various angiogenesis-related retinal diseases. Currently, bevacizumab, a recombinant humanized anti-VEGF antibody, is trailed in retinopathy of prematurity, a vasoproliferative retinal disorder in premature infants. However, the risks of systemic complications after intravitreal injection of anti-VEGF antibody in infants are not well understood. In this study, we show that intravitreally injected anti-VEGF antibody is transported into the systemic circulation into the periphery where it reduces brown fat in neonatal C57BL/6 mice. A considerable amount of anti-VEGF antibody was detected in serum after intravitreal injection. Furthermore, in interscapular brown adipose tissue, we found lipid droplet accumulation, decreased VEGF levels, loss of vascular network, and decreased expression of mitochondria-related genes, Ppargc1a and Ucp1, all of which are characteristics of "whitening" of brown fat. With increasing age and body weight, brown fat restored its morphology and vascularity. Our results show that there is a transient, but significant impact of intravitreally administered anti-VEGF antibody on brown adipose tissue in neonatal mice. We suggest that more attention should be focused on the metabolic and developmental significance of brown adipose tissue in bevacizumab treated retinopathy of prematurity infants.

No MeSH data available.


Related in: MedlinePlus

Ocular and systemic consequences of intravitreally injected anti-VEGF antibody.(A) Effects of intravitreally injected anti-VEGF antibody (1 μg/eye) on retinal neovascularization in OIR mice (n = 6). Neovascular tufts were highlighted with yellow pseudocolor on representative images of isolectin B4-stained retina. The area of neovascular tufts was normalized to total retinal area; then, the effects of anti-VEGF antibody were quantified and normalized to the control (intravitreal PBS injection). Scale bar, 200 μm. (B) Retinal VEGF concentrations at P17 with intravitreal injection of PBS or anti-VEGF antibody (n = 3). The level of VEGF was normalized to total amounts of proteins in the retina. (C) Serum concentrations of anti-VEGF antibody after intravitreal injection at P14, P17, and P21 (n = 3–6). (D) Serum VEGF concentrations after intravitreal injection of anti-VEGF antibody at P17, P21, and P28 (n = 3–6). Data are presented as mean ± SEM in graphs. Anti-VEGF, anti-VEGF antibody. NS, not significant; **, P < 0.01; ***, P <0.001 (two-tailed, unpaired T-test).
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pone.0134308.g001: Ocular and systemic consequences of intravitreally injected anti-VEGF antibody.(A) Effects of intravitreally injected anti-VEGF antibody (1 μg/eye) on retinal neovascularization in OIR mice (n = 6). Neovascular tufts were highlighted with yellow pseudocolor on representative images of isolectin B4-stained retina. The area of neovascular tufts was normalized to total retinal area; then, the effects of anti-VEGF antibody were quantified and normalized to the control (intravitreal PBS injection). Scale bar, 200 μm. (B) Retinal VEGF concentrations at P17 with intravitreal injection of PBS or anti-VEGF antibody (n = 3). The level of VEGF was normalized to total amounts of proteins in the retina. (C) Serum concentrations of anti-VEGF antibody after intravitreal injection at P14, P17, and P21 (n = 3–6). (D) Serum VEGF concentrations after intravitreal injection of anti-VEGF antibody at P17, P21, and P28 (n = 3–6). Data are presented as mean ± SEM in graphs. Anti-VEGF, anti-VEGF antibody. NS, not significant; **, P < 0.01; ***, P <0.001 (two-tailed, unpaired T-test).

Mentions: To investigate anti-angiogenic effects of anti-VEGF antibody on retinal neovascularization, we injected anti-mouse VEGF164 antibody (1 μg) into the vitreous cavity of right eyes of OIR mice at P14 (S1 Fig). OIR is a well-established animal model of retinal neovascularization in ROP [16,17]. Retinas of OIR mice demonstrate characteristics observed in those of infants with ROP: retinal hypoxia and retinal neovascularization from existing retinal vasculature. As expected, intravitreally injected anti-VEGF antibody effectively reduced the formation of neovascular tufts in OIR mice (Fig 1A). We also found reduced levels of VEGF in the retina (Fig 1B), which was likely to be the cause of reduced neovascularization.


Intravitreally Injected Anti-VEGF Antibody Reduces Brown Fat in Neonatal Mice.

Jo DH, Park SW, Cho CS, Powner MB, Kim JH, Fruttiger M, Kim JH - PLoS ONE (2015)

Ocular and systemic consequences of intravitreally injected anti-VEGF antibody.(A) Effects of intravitreally injected anti-VEGF antibody (1 μg/eye) on retinal neovascularization in OIR mice (n = 6). Neovascular tufts were highlighted with yellow pseudocolor on representative images of isolectin B4-stained retina. The area of neovascular tufts was normalized to total retinal area; then, the effects of anti-VEGF antibody were quantified and normalized to the control (intravitreal PBS injection). Scale bar, 200 μm. (B) Retinal VEGF concentrations at P17 with intravitreal injection of PBS or anti-VEGF antibody (n = 3). The level of VEGF was normalized to total amounts of proteins in the retina. (C) Serum concentrations of anti-VEGF antibody after intravitreal injection at P14, P17, and P21 (n = 3–6). (D) Serum VEGF concentrations after intravitreal injection of anti-VEGF antibody at P17, P21, and P28 (n = 3–6). Data are presented as mean ± SEM in graphs. Anti-VEGF, anti-VEGF antibody. NS, not significant; **, P < 0.01; ***, P <0.001 (two-tailed, unpaired T-test).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4520452&req=5

pone.0134308.g001: Ocular and systemic consequences of intravitreally injected anti-VEGF antibody.(A) Effects of intravitreally injected anti-VEGF antibody (1 μg/eye) on retinal neovascularization in OIR mice (n = 6). Neovascular tufts were highlighted with yellow pseudocolor on representative images of isolectin B4-stained retina. The area of neovascular tufts was normalized to total retinal area; then, the effects of anti-VEGF antibody were quantified and normalized to the control (intravitreal PBS injection). Scale bar, 200 μm. (B) Retinal VEGF concentrations at P17 with intravitreal injection of PBS or anti-VEGF antibody (n = 3). The level of VEGF was normalized to total amounts of proteins in the retina. (C) Serum concentrations of anti-VEGF antibody after intravitreal injection at P14, P17, and P21 (n = 3–6). (D) Serum VEGF concentrations after intravitreal injection of anti-VEGF antibody at P17, P21, and P28 (n = 3–6). Data are presented as mean ± SEM in graphs. Anti-VEGF, anti-VEGF antibody. NS, not significant; **, P < 0.01; ***, P <0.001 (two-tailed, unpaired T-test).
Mentions: To investigate anti-angiogenic effects of anti-VEGF antibody on retinal neovascularization, we injected anti-mouse VEGF164 antibody (1 μg) into the vitreous cavity of right eyes of OIR mice at P14 (S1 Fig). OIR is a well-established animal model of retinal neovascularization in ROP [16,17]. Retinas of OIR mice demonstrate characteristics observed in those of infants with ROP: retinal hypoxia and retinal neovascularization from existing retinal vasculature. As expected, intravitreally injected anti-VEGF antibody effectively reduced the formation of neovascular tufts in OIR mice (Fig 1A). We also found reduced levels of VEGF in the retina (Fig 1B), which was likely to be the cause of reduced neovascularization.

Bottom Line: Furthermore, in interscapular brown adipose tissue, we found lipid droplet accumulation, decreased VEGF levels, loss of vascular network, and decreased expression of mitochondria-related genes, Ppargc1a and Ucp1, all of which are characteristics of "whitening" of brown fat.With increasing age and body weight, brown fat restored its morphology and vascularity.We suggest that more attention should be focused on the metabolic and developmental significance of brown adipose tissue in bevacizumab treated retinopathy of prematurity infants.

View Article: PubMed Central - PubMed

Affiliation: Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea; Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea.

ABSTRACT
Anti-vascular endothelial growth factor (VEGF) agents are the mainstay treatment for various angiogenesis-related retinal diseases. Currently, bevacizumab, a recombinant humanized anti-VEGF antibody, is trailed in retinopathy of prematurity, a vasoproliferative retinal disorder in premature infants. However, the risks of systemic complications after intravitreal injection of anti-VEGF antibody in infants are not well understood. In this study, we show that intravitreally injected anti-VEGF antibody is transported into the systemic circulation into the periphery where it reduces brown fat in neonatal C57BL/6 mice. A considerable amount of anti-VEGF antibody was detected in serum after intravitreal injection. Furthermore, in interscapular brown adipose tissue, we found lipid droplet accumulation, decreased VEGF levels, loss of vascular network, and decreased expression of mitochondria-related genes, Ppargc1a and Ucp1, all of which are characteristics of "whitening" of brown fat. With increasing age and body weight, brown fat restored its morphology and vascularity. Our results show that there is a transient, but significant impact of intravitreally administered anti-VEGF antibody on brown adipose tissue in neonatal mice. We suggest that more attention should be focused on the metabolic and developmental significance of brown adipose tissue in bevacizumab treated retinopathy of prematurity infants.

No MeSH data available.


Related in: MedlinePlus