Maternal administration of anti-angiogenic agents, TNP-470 and Angiostatin4.5, induces fetal microphthalmia

Purpose: Agents specifically targeting the vasculature as a mode of therapy are finding increasing use in the clinic, primarily in the treatment of colon cancer (Avastin™) and age-related macular degeneration (Lucentis™). We have previously shown that maternal administration of angiogenic inhibitors (TNP-470 [O-[chloroacetylcarbamoyl]fumagillol, initially called AGM-1470], the first angiogenic inhibitor to undergo clinical trials, and Angiostatin 4.5, currently in phase I-III clinical trials) cause fetal growth restriction and/or placental abnormalities. During a rapid growth phase of ocular development in the mouse (embryonic days 12 to 19 [E12-E19]), the placenta mediates the metabolic requirements of the fetus and consequently may impact upon the growth of the highly oxygen sensitive fetal eye. Methods: We injected pregnant dams (between E10.5 – E18.5) with anti-angiogenic agents, which caused either a placental insufficiency type of IUGR (intrauterine growth restriction; i.e., TNP-470) or frank placental pathology (Angiostatin4.5 [AS4.5]), and assessed changes in absolute ocular dimensions, tissue types, and vascular profiles using stereological techniques. Results: The experiments showed that ocular volumes were significantly reduced in fetal mice where dams were treated with either TNP-470 or AS4.5. Furthermore, TNP-470 specifically caused a reduction in hyaloid blood vessel length and volume, the only intraocular vascular circulation in fetal mice. Conclusions: These experiments support the hypothesis that the angiogenic inhibitors (specifically TNP-470 and AS4.5) induce microphthalmia either indirectly by their known effects on placental morphology (and/or function) or directly via altering microvascular growth in the fetus. These results also warrant further investigation of a new experimental paradigm linking placental pathology-related fetal growth restriction and microphthalmia.