Kinetics of Angiogenic Responses in Corneal Transplantation

Inomata, Takenori MD, PhD, MBA; Mashaghi, Alireza MD, MSc, PhD; Di Zazzo, Antonio MD; Lee, Sang-Mok MD, PhD; Chiang, Homer MS; Dana, Reza MD, MSc, MPH

Author Information

Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA.

Reprints: Reza Dana, MD, MSc, MPH, Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, 20 Staniford St, Boston, MA 02114 (e-mail:[email protected]).

Supported by the National Institutes of Health/National Eye Institute Grant EY012963 (RD) and the National Eye Institute Core Grant (P30EY003790).

The authors have no conflicts of interest to disclose.

T. Inomata, A. Mashaghi, and A. Di Zazzo contributed equally to this study.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.corneajrnl.com).

Cornea36(4):p 491-496, April 2017. |DOI:10.1097/ICO.0000000000001127

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^high (blood vessels) and LYVE-1^high (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.