Laminins regulate retinal angiogenesis

Abstract

Vascular pathologies are the leading causes of acquired blindness in the developed world. While many studies sought to unravel cell-intrinsic and growth factor-mediated regulations of angiogenesis, it is only recently that the role of the basement membrane (BM) components in angiogenesis began to be explored. Several diseases with ocular manifestations are known to alter vascular BM compositions. Therefore, a detailed knowledge of the BM-mediated signals that regulate angiogenesis is of great importance. Laminins, a critical component of the BM, have been shown to regulate several aspects of angiogenesis in the retina. Our laboratory previously demonstrated that the laminin composition of the inner limiting membrane (ILM) regulates astrocyte migration, and consequently vascular expansion along the retinal surface. Here, I examined the role of γ3- and β2-containing laminins in two specific aspects of angiogenesis: 1) vascular branching and endothelial cell proliferation in the nascent vascular plexus, and 2) arterial morphogenesis in the remodeling zone. Results presented in Chapter 2 and Appendix 1 demonstrate that laminin composition of the BM is a critical regulator of microglial recruitment to the growing nascent plexus, where microglia facilitate vascular branching. Furthermore, microglia interact with the astrocyte-derived layer of the vascular BM, and that this interaction regulates iii microglial activation. The activation state of microglia, in turn, regulates endothelial cell proliferation. Results presented in Chapter 3 and Appendix 2 demonstrate that vascular BM laminins are critical regulators of arterial morphogenesis. Specifically, my results reveal a novel mechanism where γ3- containing laminins signal through dystroglycan to induce Dll4/Notch signaling in arterial endothelial cells, regulating proper arterial morphogenesis. Finally, in Appendix 3, I examined the coordinated expression of different laminin chains in the vascular BM. My preliminary results suggest that expressions of laminin α2-, α5- and γ3-chains in the retinal vascular BM are coordinately regulated with the expression of laminin β2-chain. In conclusion, this study sheds light on hitherto unexplored mechanisms by which BM laminins regulate retinal vascular development.