The Binding of CD93 to Multimerin-2 Promotes Choroidal Neovascularization

Abstract

Purpose The purpose of this study was to investigate the involvement of CD93 and Multimerin-2 in three choroidal neovascularization (CNV) models and to evaluate their contribution in the neovascular progression of age-related macular degeneration (AMD). Methods Choroidal neovascular membranes collected during surgery from AMD patients were analyzed by microscopy methods. Laser-induced CNV mouse models and choroid sprouting assays (CSAs) were carried out using the CD93 knockout mouse model. An original ex vivo CSA of vascular angiogenesis, employing choroid tissues isolated from human donors, was developed. Results In contrast to healthy choroid endothelium, hyperproliferative choroidal endothelial cells (ECs) of AMD patients expressed high levels of CD93, and Multimerin-2 was abundantly deposited along the choroidal neovasculature. CD93 knockout mice showed a significant reduced neovascularization after laser photocoagulation, and their choroidal ECs displayed a decreased ability to produce sprouts in ex vivo angiogenesis assays. Moreover, the presence of an antibody able to hamper the CD93/Multimerin-2 interaction reduced vascular sprouting in the human CSA. Conclusions Our results demonstrate that CD93 and its interaction with Multimerin-2 play an important role in pathological vascularization of the choroid, disclosing new possibilities for therapeutic intervention to neovascular AMD.

CD93 Signaling via Rho Proteins Drives Cytoskeletal Remodeling in Spreading Endothelial Cells

“…Indeed, CD93 interacts with β-dystroglycan, which is a laminin-binding protein found to be 2 of 11 upregulated in ECs of growing blood vessels within malignant tumors [9,10]. Moreover, the binding of CD93 to Multimerin-2, an endothelial-specific ECM protein [11], contributes to progression of the neovascular form of age-related macular degeneration, while in gliomas, it promotes β1 integrin activation and the fibrillar organization of fibronectin, increasing the motility of proliferating ECs [7,8,12]. Furthermore, the pathway activated by the interaction between CD93 and insulin-like growth factor binding protein 7 (IGFBP7), an ECM protein upregulated in tumor blood vessels, contributes to abnormal tumor vasculature [13].…”

Regulation of Rac1 Activation in Choroidal Endothelial Cells: Insights into Mechanisms in Age-Related Macular Degeneration

“…Studies have since demonstrated that Rac1 is activated in choroidal endothelial cells by several AMD-associated stresses, tumor necrosis factor alpha (TNFα) [26], an example of an inflammatory cytokine; vascular endothelial growth factor (VEGF) [27][28][29][30][31][32] or C-C motif chemokine 11 (CCL11) [30], angiogenic stimuli; reactive oxygen species (ROS) [26]; and 7-ketocholesterol (7KC) [29,33], an oxidized cholesterol that accumulates in human Bruch's membrane (Figure 1). A study also demonstrated CD93, a transmembrane glycoprotein [34] that is overexpressed in endothelial cells within choroidal neovascular membranes [35,36], was necessary for Rac1 activation and migration in human umbilical vein endothelial cells (HUVECs) [37]. Overall, the data support the idea that active Rac1 is an important downstream effector of AMD-associated stresses.…”

The CXCR4/miR-1910-5p/MMRN2 Axis Is Involved in Corneal Neovascularization by Affecting Vascular Permeability

“… 43 , 44 MMRN2 plays an important role in pathological vascularization of the choroid, revealing new possibilities for therapeutic intervention in neovascular AMD. 45 More important, two recent studies further elucidated the mechanism in detail. Fejza et al 46 reported that MMRN2 is also deposited in juxtaposition between ECs and pericytes as a homeostatic molecule deposited in the later stages of vessel formation and is required to maintain vascular stability.…”