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Comparative Study
.2017 Apr;36(4):491-496.
doi: 10.1097/ICO.0000000000001127.

Kinetics of Angiogenic Responses in Corneal Transplantation

Affiliations
Comparative Study

Kinetics of Angiogenic Responses in Corneal Transplantation

Takenori Inomata et al. Cornea.2017 Apr.

Abstract

Purpose: To delineate and compare the kinetics of corneal angiogenesis after high-risk (HR) versus low-risk (LR) corneal transplantation.

Methods: In mice, intrastromal sutures were placed in the recipient graft bed 2 weeks before allogeneic transplantation to induce angiogenesis and amplify the risk of graft rejection. Control (LR) graft recipients did not undergo suture placement, and thus the host bed remained avascular at the time of transplantation. Graft hemangiogenesis and opacity scores were evaluated for 8 weeks by slit-lamp biomicroscopy. Immunohistochemistry was used to measure CD31 (blood vessels) and LYVE-1 (lymphatic vessels) cells.

Results: Biphasic kinetics were observed for hemangiogenesis in both HR and LR transplant recipients using clinical and immunohistochemical assessments. The biphasic kinetics were composed of a rise-fall (phase 1) followed by a second rise (phase 2) in the degree of vessels. Compared with LR recipients, HR recipients showed higher hemangiogenesis (whole cornea and graft) throughout 8 weeks. Analyzing grafts revealed sustained presence of lymphatic vessels in HR recipients; however, lymphatic neovessels regressed in LR recipients 2 weeks posttransplantation. In contrast to HR host beds, the LR host bed microenvironment cannot sustain the growth of lymphatic neovessels in allografts, whereas it can sustain continued hemangiogenesis.

Conclusions: The sustained presence of lymphatic vessels in HR host beds can facilitate host immunity against allografts and is likely associated with ongoing higher risk of rejection of these grafts in the long term, suggesting that therapeutic interventions targeting inflammation and lymphatic vessels need to be sustained long term in the HR corneal transplant setting.

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Conflict of interest statement

Disclosure: The authors have no financial conflicts of interest.

Figures

Figure 1
Figure 1. Neovascularization, opacity, and graft survival in low-risk and high-risk transplant recipients
High-risk (HR) recipients underwent three intrastromal suture placements 14 days prior to corneal transplantation. Low-risk (LR) recipients received no sutures prior to transplantation and the corneas were left avascular and alymphatic. Corneal grafts were harvested from C57BL/6 donors and transplanted to BALB/c recipients, and the outcomes were assessed weekly for 8 weeks. (A) Representative slit-lamp images showing corneas post-transplantationin vivo. (Magnification ×25) (B) Neovascularization scores were markedly higher in HR grafts compared to LR (Two-way ANOVA, n=10/group, ***p<0.0001). We included all grafts in this statistics, irrespective of their survival scores. (C) Graft opacity scores were markedly higher in the HR grafts compared to LR (Two-way ANOVA, n=10/group, ***p<0.0001). (D) The correlation between neovascularization and graft opacity scores were examined by Spearman’s correlation test after 14 day corneal transplantation (n=140, γ =0.84, p<0.0001). (E) Kaplan-Meier survival curves show significantly decreased of survival of HR grafts compared with LR recipients (Log-rank Test, n=10/group, ***p<0.0002). (F)
Figure 2
Figure 2. Immunohistochemical assessment of hemangiogenesis
(A) Representative images showing CD31 staining of the whole cornea. (B) The percentage of the corneal area covered with blood vessels (CD31highLYVE-1low) in LR and HR recipients is shown. (C) Representative images showing CD31 staining in the grafted cornea. (D) The percentage of the graft area covered with blood vessels (CD31highLYVE-1low) in LR and HR recipients is shown. Percentage of blood vessels was calculated as follows: area covered by vessels divided by total area of cornea or graft. All data were obtained from n=10 mice/group and representative data from three independent experiments are shown.p values were calculated using two-way ANOVA test. Scale bar, 500µm.
Figure 3
Figure 3. Immunohistochemical assessment of lymphangiogenesis
(A) Representative images showing LYVE-1 staining of the whole cornea. (B) The percentage of the corneal area covered with lymphatic vessels (CD31lowLYVE-1high) in LR and HR recipients is shown. (C) Representative images showing LYVE-1 staining in the grafted cornea. (D) The percentage of the graft area covered with lymphatic vessels (CD31lowLYVE-1high) in LR and HR recipients is shown. Percentage of lymphatic vessels was calculated as follows: area covered by vessels divided by total area of cornea or graft. All data were obtained from n=10 mice/group and representative data from three independent experiments are shown.p values were calculated using two-way ANOVA test. Scale bar, 500µm.
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