Hypoxia-inducible factor-1 drives annexin A2 system-mediated perivascular fibrin clearance in oxygen-induced retinopathy in mice

Abstract

Oxygen-induced retinopathy (OIR) is a well-characterized model for retinopathy of prematurity, a disorder that results from rapid microvascular proliferation after exposure of the retina to high oxygen levels. Here, we report that the proliferative phase of OIR requires transcriptional induction of the annexin A2 (A2) gene through the direct action of the hypoxiainducible factor-1 complex. We show, in addition, that A2 stabilizes its binding partner, p11, and promotes OIR-related angiogenesis by enabling clearance of perivascular fibrin. Adenoviral-mediated restoration of A2 expression restores neovascularization in the oxygen-primed Anxa2 ؊/؊ retina and reinstates plasmin generation and directed migration in cultured Anxa2 ؊/؊ endothelial cells. Systemic depletion of fibrin repairs the neovascular response to high oxygen treatment in the Anxa2 ؊/؊ retina, whereas inhibition of plasminogen activation dampens angiogenesis under the same conditions. These findings show that the A2 system enables retinal neoangiogenesis in OIR by enhancing perivascular activation of plasmin and remodeling of fibrin. These data suggest new potential approaches to retinal angiogenic disorders on the basis of modulation of perivascular fibrinolysis. (Blood. 2011;118(10): 2918-2929) IntroductionRetinopathy of prematurity (ROP) is the main cause of severe visual impairment in children in the developed world. 1 A vascular proliferative disorder that affects preterm and low-birth weight infants on exposure to supraphysiologic oxygen tension, ROP is increasing in incidence with the greater availability of neonatal intensive care, and more frequent survival of very-low-birth weight infants. In the initial, vaso-obliterative phase of ROP, high oxygen exposure provokes endothelial cell death because of oxidative injury, nitrative stress, and suppression of oxygen-related growth factors. 2 In the second phase, the resulting retinal ischemia leads to neovascularization characterized by excessive proliferation and vitreal invasion of blood vessels. This pathologic response arises when neurons and supporting astrocytes become severely metabolically deprived because of vaso-obliteration and produce exaggerated amounts of oxygen-regulated angiogenic factors, such as VEGF and erythropoietin. These agents stimulate the regrowth of abnormal vessels that proliferate toward the vitreous, can form a fibrous scar, and, on contraction, can apply tractional forces that ultimately may detach the retina from its underlying pigment epithelium. Scarring and retinal detachment can lead to vision loss and blindness. Current preventive measures for ROP include restriction of tissue oxygenation and the use of antioxidants, whereas standard treatment for established disease requires ablative laser photocoagulation or cryotherapy. Newer therapies with VEGF-neutralizing antibodies appear promising, but their effects on retinal ganglion cell integrity, the developing cerebral vasculature, and long-term visual acuity and visual fields are unknown. 2 Annexin A2 is a cell...

Disruption of Kv1.3 Channel Forward Vesicular Trafficking by Hypoxia in Human T Lymphocytes

“…This effect was specific to Kv1.3 channels (the protein levels of SK2, a K Ca channel expressed in Jurkat T cells, were unchanged) and to the Kv1.3 pore forming ␣ subunit (the expression of the auxiliary Kv␤2 subunit was unchanged) (5). Herein we showed that the decrease in Kv1.3 surface expression during hypoxia is also specific of this membrane protein because, in accordance with previous studies, the expression of the plasma membrane protein cadherin remained unaltered (26,27).…”

“…The effect of hypoxia on Kv1.3 surface expression was compared with that on the plasma membrane protein cadherin (26,27). We found no effect of hypoxia on cadherin.…”

Annexins – insights from knockout mice

“…This comprises matrigel implant, corneal pocket and oxygen-induced retinopathy, the latter mimicking aspects of diabetic retinopathy (Ling et al, 2004;Huang et al, 2011;Hedhli et al, 2012).…”

Sensing of cell stress by human γδ TCR-dependent recognition of annexin A2

“…It can exist as a monomer or as heterotetrameric complexes with the S100A10 protein, which enhances its membrane phospholipid binding affinity. In our hands, the highest expression of annexin A2 observed at the cell surface was achieved by placing cells under hypoxia, probably because it combines both membrane translocation and an increase in annexin A2 gene expression, which has been shown to be dependent on HIF-1 (23). Cellular reoxygenation after hypoxia is followed by ROS burst, and inhibiting ROS production using antioxidant NAC decreased stress-induced annexin A2 surface expression.…”

“…Second, despite the absence of a transmembrane domain, intracellular annexin A2 can swiftly translocate to cell surface upon stress signals (25) in agreement with the increase of FMS-01 binding on glioblastoma cells treated for only 30 min at 42°C. In endothelial cells, annexin A2 translocation is obtained, in vitro but also in vivo, within minutes in response to heat stress, thrombin exposure, or hypoxia and relies on annexin A2 phosphorylation (21)(22)(23). Third, consistent with γδ T-cell responses to tissue injury (26) annexin A2 plays a role in membrane repair and wound healing (27), which is supposedly because of an intracellular rise in Ca 2+ upon membrane damage (28).…”