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Endothelin-2-mediated protection of mutant photoreceptors in inherited photoreceptor degeneration.

Bramall AN, Szego MJ, Pacione LR, Chang I, Diez E, D'Orleans-Juste P, Stewart DJ, Hauswirth WW, Yanagisawa M, McInnes RR - PLoS ONE (2013)

Bottom Line: Together, these findings suggest that increased Edn2 expression is protective to mutant PRs.Notably, increased expression of the FGF2 protein in Tg(RHO P347S) PRs was ablated in Tg(RHO P347S); Edn2(-/-) retinas.Our findings indicate that the increased expression of PR Edn2 increases PR survival, and suggest that the Edn2-dependent increase in PR expression of FGF2 may contribute to the augmented survival.

View Article: PubMed Central - PubMed

Affiliation: Program in Developmental Biology, The Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.

ABSTRACT
Expression of the Endothelin-2 (Edn2) mRNA is greatly increased in the photoreceptors (PRs) of mouse models of inherited PR degeneration (IPD). To examine the role of Edn2 in mutant PR survival, we generated Edn2(-/-) mice carrying homozygous Pde6b(rd1) alleles or the Tg(RHO P347S) transgene. In the Edn2(-/-) background, PR survival increased 110% in Pde6b(rd1/rd1) mice at post-natal (PN) day 15, and 60% in Tg(RHO P347S) mice at PN40. In contrast, PR survival was not increased in retinal explants of Pde6b(rd1/rd1) ; Edn2(-/-) mice. This finding, together with systemic abnormalities in Edn2(-/-) mice, suggested that the increased survival of mutant PRs in the Edn2(-/-) background resulted at least partly from the systemic EDN2 loss of function. To examine directly the role of EDN2 in mutant PRs, we used a scAAV5-Edn2 cDNA vector to restore Edn2 expression in Pde6b(rd1/rd1) ; Edn2(-/-) PRs and observed an 18% increase in PR survival at PN14. Importantly, PR survival was also increased after injection of scAAV5-Edn2 into Pde6b(rd1/rd1) retinas, by 31% at PN15. Together, these findings suggest that increased Edn2 expression is protective to mutant PRs. To begin to elucidate Edn2-mediated mechanisms that contribute to PR survival, we used microarray analysis and identified a cohort of 20 genes with >4-fold increased expression in Tg(RHO P347S) retinas, including Fgf2. Notably, increased expression of the FGF2 protein in Tg(RHO P347S) PRs was ablated in Tg(RHO P347S); Edn2(-/-) retinas. Our findings indicate that the increased expression of PR Edn2 increases PR survival, and suggest that the Edn2-dependent increase in PR expression of FGF2 may contribute to the augmented survival.

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Systemic erythropoietin (EPO) and retinal vascular endothelial growth factor (VEGF) is increased in Edn2−/− mice.At PN21, serum EPO was increased 11-fold in Edn2−/− vs. Edn2+/+ mice (n = 7; p<0.005) (A) and retinal VEGF was increased 4-fold (n = 4; p<0.005) (B). EPO and VEGF were both measured using ELISA assays. Error bars indicate SEM.
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pone-0058023-g003: Systemic erythropoietin (EPO) and retinal vascular endothelial growth factor (VEGF) is increased in Edn2−/− mice.At PN21, serum EPO was increased 11-fold in Edn2−/− vs. Edn2+/+ mice (n = 7; p<0.005) (A) and retinal VEGF was increased 4-fold (n = 4; p<0.005) (B). EPO and VEGF were both measured using ELISA assays. Error bars indicate SEM.

Mentions: To identify possible systemically-mediated causes of the increased in vivo survival of PRs in Tg(RHO P347S); Edn2−/− and Pde6brd1/rd1; Edn2−/− retinas, we examined Edn2−/− mice for gross morphological abnormalities. Among other phenotypes, we found that Edn2−/− mice have defective lungs leading to systemic hypoxia (unpublished data). The hypoxia was associated with an 11-fold increase in erythropoietin (EPO) levels at PN21 (n = 7; p<0.05)(Fig. 3A). Moreover, vascular endothelial growth factor (VEGF) levels in Edn2−/− retinas were 4.2-fold elevated (n = 4; p<0.05), an increase consistent with the presence of retinal hypoxia (Fig. 3B). The presence of systemic and probable retinal hypoxia in Edn2−/− mice suggests that hypoxia may be at least partially responsible for the increased in vivo PR survival in Pde6brd1/rd1; Edn2−/− and Tg(RHO P347S); Edn2−/− retinas, since we have previously demonstrated that hypoxia increases PR survival in Pde6brd1/rd1 retinal explants [42].


Endothelin-2-mediated protection of mutant photoreceptors in inherited photoreceptor degeneration.

Bramall AN, Szego MJ, Pacione LR, Chang I, Diez E, D'Orleans-Juste P, Stewart DJ, Hauswirth WW, Yanagisawa M, McInnes RR - PLoS ONE (2013)

Systemic erythropoietin (EPO) and retinal vascular endothelial growth factor (VEGF) is increased in Edn2−/− mice.At PN21, serum EPO was increased 11-fold in Edn2−/− vs. Edn2+/+ mice (n = 7; p<0.005) (A) and retinal VEGF was increased 4-fold (n = 4; p<0.005) (B). EPO and VEGF were both measured using ELISA assays. Error bars indicate SEM.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585171&req=5

pone-0058023-g003: Systemic erythropoietin (EPO) and retinal vascular endothelial growth factor (VEGF) is increased in Edn2−/− mice.At PN21, serum EPO was increased 11-fold in Edn2−/− vs. Edn2+/+ mice (n = 7; p<0.005) (A) and retinal VEGF was increased 4-fold (n = 4; p<0.005) (B). EPO and VEGF were both measured using ELISA assays. Error bars indicate SEM.
Mentions: To identify possible systemically-mediated causes of the increased in vivo survival of PRs in Tg(RHO P347S); Edn2−/− and Pde6brd1/rd1; Edn2−/− retinas, we examined Edn2−/− mice for gross morphological abnormalities. Among other phenotypes, we found that Edn2−/− mice have defective lungs leading to systemic hypoxia (unpublished data). The hypoxia was associated with an 11-fold increase in erythropoietin (EPO) levels at PN21 (n = 7; p<0.05)(Fig. 3A). Moreover, vascular endothelial growth factor (VEGF) levels in Edn2−/− retinas were 4.2-fold elevated (n = 4; p<0.05), an increase consistent with the presence of retinal hypoxia (Fig. 3B). The presence of systemic and probable retinal hypoxia in Edn2−/− mice suggests that hypoxia may be at least partially responsible for the increased in vivo PR survival in Pde6brd1/rd1; Edn2−/− and Tg(RHO P347S); Edn2−/− retinas, since we have previously demonstrated that hypoxia increases PR survival in Pde6brd1/rd1 retinal explants [42].

Bottom Line: Together, these findings suggest that increased Edn2 expression is protective to mutant PRs.Notably, increased expression of the FGF2 protein in Tg(RHO P347S) PRs was ablated in Tg(RHO P347S); Edn2(-/-) retinas.Our findings indicate that the increased expression of PR Edn2 increases PR survival, and suggest that the Edn2-dependent increase in PR expression of FGF2 may contribute to the augmented survival.

View Article: PubMed Central - PubMed

Affiliation: Program in Developmental Biology, The Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.

ABSTRACT
Expression of the Endothelin-2 (Edn2) mRNA is greatly increased in the photoreceptors (PRs) of mouse models of inherited PR degeneration (IPD). To examine the role of Edn2 in mutant PR survival, we generated Edn2(-/-) mice carrying homozygous Pde6b(rd1) alleles or the Tg(RHO P347S) transgene. In the Edn2(-/-) background, PR survival increased 110% in Pde6b(rd1/rd1) mice at post-natal (PN) day 15, and 60% in Tg(RHO P347S) mice at PN40. In contrast, PR survival was not increased in retinal explants of Pde6b(rd1/rd1) ; Edn2(-/-) mice. This finding, together with systemic abnormalities in Edn2(-/-) mice, suggested that the increased survival of mutant PRs in the Edn2(-/-) background resulted at least partly from the systemic EDN2 loss of function. To examine directly the role of EDN2 in mutant PRs, we used a scAAV5-Edn2 cDNA vector to restore Edn2 expression in Pde6b(rd1/rd1) ; Edn2(-/-) PRs and observed an 18% increase in PR survival at PN14. Importantly, PR survival was also increased after injection of scAAV5-Edn2 into Pde6b(rd1/rd1) retinas, by 31% at PN15. Together, these findings suggest that increased Edn2 expression is protective to mutant PRs. To begin to elucidate Edn2-mediated mechanisms that contribute to PR survival, we used microarray analysis and identified a cohort of 20 genes with >4-fold increased expression in Tg(RHO P347S) retinas, including Fgf2. Notably, increased expression of the FGF2 protein in Tg(RHO P347S) PRs was ablated in Tg(RHO P347S); Edn2(-/-) retinas. Our findings indicate that the increased expression of PR Edn2 increases PR survival, and suggest that the Edn2-dependent increase in PR expression of FGF2 may contribute to the augmented survival.

Show MeSH
Related in: MedlinePlus