Pathologic Angiogenesis Recapitulation of Microvascular Development

Development of the retinal vasculature is tightly regulated and highly dependent on cell-to-cell and cell-to-matrix interactions. For example, during retinal development, astrocytes transiently express VEGF as they migrate across the ganglion cell layer, preceding the formation of the superficial layer of retinal microvessels. Müller cells also express VEGF and direct a deeper layer of retinal microvascu-lar morphogenesis. Blinding diseases, such as diabetic retinopathy, age-related macular degeneration, or neovascu-lar glaucoma are directly related to aberrant angiogenic responses, which deploy common features of developmental angiogenesis, including ischemia and increased vascular permeability. For example, in diabetic retinopathy, pathological changes in the retinal vasculature yield proliferation of endothelial cells, and the loss or de-differentiation of pericytes is believed to be causally linked to the pathologic angiogenic cascade.

The correlation between the absence of pericytes and retinal neovascularization in diabetic retinopathy led to the hypothesis that pericytes exert a suppressive influence in capillary growth. Pericytes and endothelial cells share and coproduce a common basement membrane through which direct cell-to-cell contact can be achieved. Consistent with this concept was the ultrastructural observation that pericyte association with the developing capillary marked the cessation of vessel growth. Pericyte growth and recruitment is positively regulated by PDGF-b, and recently it was reported that endothelium-restricted ablation of PDGF-b generates viable mice with extensive inter- and intra-individual variation in the density of pericytes throughout the CNS, including retina. This strong inverse correlation between pericyte density and the formation of a range of retinal microvascular abnormalities suggests that pericyte depletion may be sufficient to cause retinopathy, at least, in mice. Evidence suggests that at least some of the retinal pericytes are lost during nonproliferative diabetic retinopathy as a result of apoptosis, presumably secondary to hyper-glycemic episodes. However, based on earlier work carried out in the lab, we also suspect that pericyte loss is caused by their de-differentiation and concomitant dissociation from the retinal endothelium. We further speculate that pericyte apoptosis might ensue as a result of either mechanism; alterations in the retinal microvascular basement membrane are also likely to be contributory, all events leading to a similarly dysfunctional retinal microvasculature. Although these mechanisms by which pericytes suppress endothelial cell proliferation and/or stabilize capillaries have not been completely elucidated, coculture of pericytes with endothelial cells indicate that growth inhibition is achieved in a contact-and TGF-b-dependent process. It is our working hypothesis that signaling through the retinal microvascular isoactin network orchestrates the retinal microvascular remodeling required for developmental and pathologic retinal angio-genesis. Ongoing experiments will not only directly test this hypothesis, but results will also reveal the molecular switches controlling developmental and pathologic angiogenesis.

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Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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