The Wnt inhibitor Apcdd1 controls vascular remodeling and barrier properties of blood vessels in the developing retina
Coordinating angiogenesis with the acquisition of specialized endothelial cell properties is essential for proper vascular function. Within the retina, endothelial cells form a blood- retina barrier that restricts paracellular diffusion of molecules by creating high-resistance tight junctions, and confers a low rate of transcytosis. Despite the importance for retinal function, how angiogenesis, vascular remodeling and barrier maturation are coordinated remains incompletely characterized. One essential pathway for retinal angiogenesis and barrier formation is the canonical Wnt signaling pathway, which activates β-catenin via interactions between Norrin and the Fz4/Lrp5 signaling complex. The focus of my thesis research has been to investigate if Apcdd1, a negative regulator of Wnt/β-catenin signaling expressed in retinal endothelial cells, regulates angiogenesis and blood-retina barrier development. I show that loss of Apcdd1 increased β-catenin activity in retinal endothelial cells resulting in hypervascularization due to decreased vessel pruning. In the retina, Apcdd1-deficient mice show increased levels of the tight junction protein Occludin and decreased paracellular permeability (Chapter 3). The early postnatal striatum and cortex of Apcdd1-/- mice show no difference in vessel density (Chapter 4), suggesting that regional differences exist in the pathways that regulate angiogenesis throughout the central nervous system and Apcdd1 may be a more efficient inhibitor of Norrin/β-catenin signaling rather than Wnt/β-catenin signaling. Finally, I provide preliminary data on the generation of an endothelial-specific gain-of-function transgenic mouse to determine the effect of Apcdd1 overexpression on retina angiogenesis and blood-retina barrier development (Chapter 5). Overall, these data suggest that distinct levels of canonical Wnt signaling, controlled by Apcdd1, regulate angiogenesis, vascular remodeling and barrier maturation in retinal blood vessels.