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G. A. Lutty, T. Hasegawa, C. Merges, D. S. McLeod; VEGF-A and Angiopoietins in Development of Fetal Human Ocular Vasculatures. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5908.
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Development of the human ocular vasculatures likely requires a variety of growth factors and receptors. It was previously reported that VEGF and angiopoietin 1 requisitely collaborate during embryonic blood vessel development in mouse. Therefore, we determined the localization of angiopoietins (Ang-1 and -2) and their receptor Tie-2 and vascular endothelial cell growth factor-A (VEGF) and its type 1 and 2 receptors (R1 and R2) during the development of three human ocular vasculatures: retina, choroid, and hyaloid (HV) or fetal vasculature of vitreous.
Alkaline phosphatase immunohistochemistry was performed for the VEGF and angiopoietin receptors and ligands and CD34 was used as a blood vessel marker on cryopreserved embryonic and fetal human eyes from 6-23 weeks gestation (WG).
The HV had immunoreactivity for VEGF and its receptors, and Ang1 and 2 and Tie-2 were present from 6-14 WG when its regression occurred. The choroid had many Ang2+ single cells at 7 WG but little immunoreactivity thereafter except in large blood vessels. Ang-1 was diffuse in all choroidal vessels at all time points. Tie-2 expression in choroidal vessels was weak at 7 WG but prominent after 12WG. VEGF was associated with choriocapillaris (CC) after 16 WG but VEGF-R2 was associated with choroidal blood vessels at all time points in development. VEGF-R1 expression increased with age in CC and large choroidal vessels. VEGF and Ang-2 expression patterns in retina were very similar throughout the time course, while Tie-2 and Ang-1 had similar patterns throughout inner retina. Apparent vascular precursors, angioblasts, in inner avascular retina were VEGF-R2 and R1 positive. When retina became vascularized at 14WG, Tie-2 and both VEGF receptors were associated with the retinal vasculature.
VEGF-A and the angiopoietins are prominent in the HV and retina during vascular development. However, the three ocular vasculatures differ in expression of angiopoietins, Tie-2, VEGF and its receptors even though the CC and HV both develop by hemo-vasculogenesis. Vasculogenesis in retina involves VEGF-R2+/Tie-2- angioblasts. Almost identical localization suggests that VEGF may stimulate production of Ang-2 as demonstrated in vitro in endothelial cells (Oh et al., JBC 274:15739, 1999).
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