Abstract
Apoptosis plays a central role in developmental and pathological angiogenesis and vessel regression. Bim is a pro-apoptotic Bcl-2 family member that plays a prominent role in both developmental and pathological ocular vessel regression, and neovascularization. Endothelial cells (EC) and pericytes (PC) each play unique roles during vascular development, maintenance and regression. We recently showed that germline deletion of Bim results in persistent hyaloid vasculature, increased retinal vascular density and prevents retinal vessel regression in response to hyperoxia. To determine whether retinal vascular regression is attributable to Bim expression in EC or PC we generated mice carrying a conditional Bim allele (BimFlox/Flox) and VE-cadherin-cre (BimEC mice) or Pdgfrb-cre (BimPC mice). BimEC and BimPC mice demonstrated attenuated hyaloid vessel regression and postnatal retinal vascular remodeling. We also observed decreased retinal vascular apoptosis and proliferation. Unlike global Bim -/- mice, mice conditionally lacking Bim in EC or PC underwent hyperoxia-mediated vessel obliteration and subsequent retinal neovascularization during oxygen-induced ischemic retinopathy similar to control littermates. Thus, understanding the cell autonomous role Bim plays in the retinal vascular homeostasis will give us new insight into how to modulate pathological retinal neovascularization and vessel regression to preserve vision.
Highlights
Retinal vascular cell death or apoptosis can be positively or negatively influenced by Bcl-2 family members
Attenuation of hyaloid vessel regression in BimFlox/Flox allele which also expressed VE-cadherincre (BimEC) or BimPC mice The immature lens, retina and vitreous are nourished by the pupillary membrane (PM) and hyaloid vessels-hyaloid arteries, tunica vasculosa lentis (TVL), and vasa hyaloidea propria (VHP) [20]
We show persistence of the hyaloid vasculature in BimEC and BimPC mice suggesting that hyaloid vascular cells must be susceptible to apoptosis for complete regression to occur
Summary
Retinal vascular cell death or apoptosis can be positively or negatively influenced by Bcl-2 family members. OIR is characterized by attenuation of retinal vascular development and apoptosis-driven loss of existing blood vessels [7] This is followed by the ischemic retina initiating a proangiogenic response, including increased VEGF production resulting in pathological growth of new blood vessels. We have previously shown that lack of Bim expression resulted in increased VEGF production in retinal vascular cells [2, 8, 9], which protected the developing retinal vasculature from hyperoxia-mediated vessel obliteration and subsequent neovascularization [6]. Unlike global Bim -/- mice, substantial hyperoxia-mediated vessel obliteration and subsequent neovascularization was observed following OIR in both BimEC and BimPC mice [6] These studies increase our understanding of how modulating apoptosis of specific vascular cells influences normal development and pathological ocular conditions in which vessel regression may be of therapeutic benefit
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