Angiogenesis and lymphangiogenesis in corneal transplantation–A review

Zhong, Wei; Montana, Mario; Santosa, Samuel M.; Isjwara, Irene D.; Huang, Yao Zhi; Han, Kyu-Yeon; O'Neil, Christopher; Wang, Ashley; Cortina, María Soledad; Cruz, José de la; Zhou, Qiang; Rosenblatt, Mark I.; Chang, Jin-Hong; Azar, Dimitri T.

doi:10.1016/j.survophthal.2017.12.008

Cited by 63 publications

(58 citation statements)

References 189 publications

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“…The binding of VEGF-A and VEGF-B to VEGFR-1 and VEGFR-2 drives angiogenesis, whereas the binding of VEGF-C and VEGF-D to VEGFR-2 and VEGFR-3 drives lymphangiogenesis [91,[98][99][100]. The complex interactions between VEGFs and VEGFRs exhibit sophisticated control over angiogenesis and lymphangiogenesis [101].…”

Section: Prior To Transplantationmentioning

confidence: 99%

Variable Responses to Corneal Grafts: Insights from Immunology and Systems Biology

Zazzo

Lee

Sung

et al. 2020

JCM

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Corneal grafts interact with their hosts via complex immunobiological processes that sometimes lead to graft failure. Prediction of graft failure is often a tedious task due to the genetic and nongenetic heterogeneity of patients. As in other areas of medicine, a reliable prediction method would impact therapeutic decision-making in corneal transplantation. Valuable insights into the clinically observed heterogeneity of host responses to corneal grafts have emerged from multidisciplinary approaches, including genomics analyses, mechanical studies, immunobiology, and theoretical modeling. Here, we review the emerging concepts, tools, and new biomarkers that may allow for the prediction of graft survival.

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Section: Prior To Transplantationmentioning

confidence: 99%

Variable Responses to Corneal Grafts: Insights from Immunology and Systems Biology

Zazzo

Lee

Sung

et al. 2020

JCM

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“…2A) can result from physical or chemical injury, surgical procedures, foreign body reactions, localized hypoxia, limbal stem cell deficiency, or from infections. 1,27,28 When successfully treated, the regression of pathologic vessels leaves behind threadlike strands in the regressed region after antiangiogenic treatment (Fig. 2B), but the structural and flow characteristics of these features, and their fate during re-stimulation of neovascularization are unknown.…”

Section: Human Case Of Corneal Neovascularization and Ghost Vessels Fmentioning

confidence: 99%

Repeat Corneal Neovascularization is Characterized by More Aggressive Inflammation and Vessel Invasion Than in the Initial Phase

Mukwaya

Mirabelli

Lennikov

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Treatment of corneal neovascularization can lead to vessel regression and recovery of corneal transparency. Here, we examined the response of the cornea to a repeated stimulus after initial vessel regression comparing the second wave of neovascularization with the first. METHODS. Corneal neovascularization was induced by surgical suture placement in the rat cornea for 7 days, followed by suture removal and a 30-day regression period. Corneas were then re-sutured and examined for an additional 4 days. Longitudinal slit-lamp imaging, in vivo confocal microscopy, and microarray analysis of global gene expression was conducted to assess the inflammatory and neovascularization response. Inhibitory effect of topical dexamethasone for repeat neovascularization was assessed. RESULTS. After initial robust neovascularization, 30 days of regression resulted in the recovery of corneal transparency; however, a population of barely functional persistent vessels remained at the microscopic level. Upon re-stimulation, inflammatory cell invasion, persistent vessel dilation, vascular invasion, and gene expression of Vegfa, Il1b, Il6, Ccl2, Ccl3, and Cxcl2 all doubled relative to initial neovascularization. Repeat neovascularization occurred twice as rapidly as initially, with activation of nitric oxide and reactive oxygen species, matrix metalloproteinase, and leukocyte extravasation signaling pathways, and suppression of antiinflammatory LXR/RXR signaling. While inhibiting initial neovascularization, a similar treatment course of dexamethasone did not suppress repeat neovascularization. CONCLUSIONS. Persistent vessels remaining after the initial resolution of neovascularization can rapidly reactivate to facilitate more aggressive inflammation and repeat neovascularization, highlighting the importance of achieving and confirming complete vessel regression after an initial episode of corneal neovascularization.

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“…There is rarely spontaneous corneal NV in response to DED experimentally or clinically. Corneal avascularity is not a simple and passive lack of blood vessels; on the contrary, it is a highly and tightly regulated process, mediated by a plethora of anti‐angiogenic factors to actively suppress and regress NV . This intrinsically high threshold to develop NV is likely the reason for the lack of spontaneous NV during DED.…”

Section: Discussionmentioning

confidence: 99%

“…The normal cornea is avascular and densely innervated, rendering it a unique model to interrogate neuro‐vascular interaction. Infection and inflammation of the ocular surface can induce corneal neovascularization (NV) and nerve inflammation/degeneration . Corneal epithelium, stromal keratocytes, limbal stem cells, and infiltrating leukocytes have all been implicated in corneal angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Sensory neurons directly promote angiogenesis in response to inflammation via substance P signaling

2020

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Blood vessels and nerves travel together to supply most tissues in the body. However, there is a knowledge gap in the mechanisms underlying the direct regulation of angiogenesis by nerves. In the current study, we examined the regulation of angiogenesis by sensory nerves in response to inflammation using the cornea, a normally avascular and densely innervated ocular tissue, as a model. We used desiccating stress as an inflammatory stimulus in vivo and found that sub‐basal and epithelial nerve densities in the cornea were reduced in dry eye disease (DED). We established a co‐culture system of trigeminal ganglion sensory neurons and vascular endothelial cells (VEC) and found that neurons isolated from mice with DED directly promoted VEC proliferation and tube formation compared with normal controls. In addition, these neurons expressed and secreted higher levels of substance P (SP), a proinflammatory neuropeptide. SP potently promoted VEC activation in vitro and blockade of SP signaling with spantide I, an antagonist of SP receptor Neurokinin‐1, significantly reduced corneal neovascularization in vivo. Spantide I and siRNA knockdown of SP abolished the promotion of VEC activation by DED neurons in vitro. Taken together, our data suggested that sensory neurons directly promote angiogenesis via SP signaling in response to inflammation in the cornea.

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Angiogenesis and lymphangiogenesis in corneal transplantation–A review

Cited by 63 publications

References 189 publications

Variable Responses to Corneal Grafts: Insights from Immunology and Systems Biology

Variable Responses to Corneal Grafts: Insights from Immunology and Systems Biology

Repeat Corneal Neovascularization is Characterized by More Aggressive Inflammation and Vessel Invasion Than in the Initial Phase

Sensory neurons directly promote angiogenesis in response to inflammation via substance P signaling

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