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Allen C Clermont, Qunfang Zhou, Nivetha Murugesan, Ward Fickweiler, Edward P Feener; Plasma kallikrein (PKal) deficiency ameliorates the effects of vascular endothelial growth factor (VEGF) on retinal hyperpermeability and edema.. Invest. Ophthalmol. Vis. Sci. 2014;55(13):594.
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Previously, we have shown that PKal deficiency is protective against diabetes induced retinal hyperpermeability. Although proteomics have shown that PKal and VEGF are elevated in the vitreous of patients with diabetic macular edema (DME), the interactions between these pathways are not fully understood. This study examines the effects of intravitreal VEGF on retinal hyperpermeability and thickness in a mouse model of PKal deficiency.
Plasma prekallikrein, Klkb1, knockout (KO) and Wild-type (WT) littermates were used for these studies. Basal parameters were assessed for blood pressure, body composition (DEXA), and glucose tolerance. 10ng of VEGF or PBS was injected into eyes of the mice. After 24 hrs, retina were imaged by spectral domain optical coherence tomography (Bioptigen) for retinal thickness. Retinal vascular permeability (RVP) was measured by Evans-blue permeation. In a separate study, 2ng of VEGF or PBS was injected into Sprague Dawley rat eyes and retina harvested after 24 hrs for Western blot of PKal and Factor XII (FXII).
WT and KO mice had similar values for systolic blood pressure (109±2 v 106±1 mmHg), fasting blood glucose (99±5 v 110±14 mg/dl) and body fat composition (3.9±0.3 v 3.6±0.3 g). Plasma levels of FXII and C1 inhibitor were similar between WT and KO. VEGF increased total retinal thickness by 19.2% (p<0.001) compared to 4% by PBS in WT mice. VEGF increased thickness by 10.5% (p<0.001) compared to 4.2% by PBS in KO mice. Overall, VEGF-induced retinal thickness was reduced from 245±4um for WT (n=10) to 228±3um for KO (n=10) mice (p=0.002). In WT mice, VEGF increased RVP by 4.3 fold (81.8±18 v 15.3±3 uL/g/h, p=0.001) compared to PBS. In KO mice, VEGF increased RVP by 1.6 fold (41.1±7 ul/g/h) representing a 61% decrease (p=0.028) in RVP compared to VEGF in WT mice. In rat retina, VEGF injection increased FXII by 46% (p=0.007) and PKal by 39% (p=0.055) compared to PBS treated retina.
Plasma prekallikrein deficiency in mice is well-tolerated. VEGF stimulated hyper-RVP and thickness are reduced in the Klkb1 KO mouse model indicating that PKal contributes to VEGF-vascular dysfunction and edema. VEGF injection increased retinal levels of Kallikrein-kinin system components. These results suggest that PKal inhibition may provide a therapeutic opportunity to reduce the effects of VEGF in DME.
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