Although insulin-like growth factor 1 (IGF-1) has been associated with retinopathy, proof of a direct relationship has been lacking. Here we show that an IGF-1 receptor antagonist suppresses retinal neovascularization in vivo, and infer that interactions between IGF-1 and the IGF-1 receptor are necessary for induction of maximal neovascularization by vascular endothelial growth factor (VEGF). IGF-1 receptor regulation of VEGF action is mediated at least in part through control of VEGF activation of p44/42 mitogen-activated protein kinase, establishing a hierarchical relationship between IGF-1 and VEGF receptors. These findings establish an essential role for IGF-1 in angiogenesis and demonstrate a new target for control of retinopathy. They also explain why diabetic retinopathy initially increases with the onset of insulin treatment. IGF-1 levels, low in untreated diabetes, rise with insulin therapy, permitting VEGF-induced retinopathy.
The immunology of pregnancy is complex and poorly defined. During the complex process of pregnancy, macrophages secrete many cytokines/chemokines and play pivotal roles in the maintenance of maternal-fetal tolerance. Here, we summarized the current knowledge of macrophage polarization and the mechanisms involved in physiological or pathological pregnancy processes, including miscarriage, preeclampsia, and preterm birth. Although current evidence provides a compelling argument that macrophages are important in pregnancy, our understanding of the roles and mechanisms of macrophages in pregnancy is still rudimentary. Since macrophages exhibit functional plasticity, they may be ideal targets for therapeutic manipulation during pathological pregnancy. Additional studies are needed to better define the functions and mechanisms of various macrophage subsets in both normal and pathological pregnancy.
The purpose of this study was to evaluate the function of extravascular vascular endothelial growth factor (VEGF) receptors in developing neural retina. VEGF is routinely described as a vascular endothelial cell‐specific mitogen, and VEGF receptor 1 (VEGFR‐1) and VEGF receptor 2 (VEGFR‐2) are described as endothelial cell specific, but there is evidence that these VEGF receptors are found outside the vasculature in neural tissue. The developing eye presents a unique opportunity to examine the function of VEGF in neural tissue alone. The peripheral retina is normally avascular at birth and becomes vascularized over the first 2 wk after birth. We localized VEGFR‐1 and ‐2 mRNA and protein to extravascular neuronal tissue during early retinal development. Avascular cornea also expresses these receptors. Inhibition of VEGFR‐1 and ‐2 in vivo with a specific small‐molecule tyrosine kinase antagonist, SU5416, inhibits development of the nonvascularized immature retina, resulting in cell loss in the inner retina, including the inner nuclear layer containing Muller cells and the ganglion cell layer containing astrocytes. Isolated retinal Muller cells express both VEGF receptors. VEGF stimulation activates MAPK, which is abrogated with inhibition of the receptors. We conclude that VEGFR‐ 1 and ‐2 are necessary for normal neural retinal development independent of vascular development.
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