Further Development 18.13: Anti-Angiogenesis in Normal and Abnormal Development

Intermediate and Lateral Plate Mesoderm: Heart, Blood, and Kidneys

Like any powerful process in development, angiogenesis has to be powerfully regulated. Blood vessel for-mation must be signaled when to cease, and in some tissues, blood vessel formation must be prevented. For example, the cornea of most mammals is avascular.1 This absence of blood vessels allows the transparency of the cornea and optical acuity. The cornea appears to have two ways of keeping blood vessels out of the cornea. The first mechanism involves preventing the release of VEGF from the extracellular matrix in which it is stored (Seo et al. 2012). In addition, Ambati and colleagues (2006) have shown that the cornea secretes a soluble form of the VEGF receptor that “traps” VEGF and prevents angiogenesis in the cornea.

Soluble VEGF receptor also appears to be one of the normal mechanisms for regulating the increased for-mation of vasculature in the uterus during pregnancy. However, if too much soluble VEGF receptor is pro-duced during pregnancy, there can be a dramatic reduction of normal angiogenesis. The spiral arteries that supply the fetus with nutrition fail to form, and the capillary bed of the kidneys is reduced. These events are thought to be a major cause of preeclampsia, a condition of pregnancy characterized by hypertension and poor renal filtration (both of which are kidney problems) and fetal distress. Preeclampsia is the leading cause of premature birth and a major cause of maternal and fetal deaths (Levine et al. 2006; Mutter and Karumanchi 2008).

Too much VEGF can also be dangerous. Abnormal blood vessel formation occurs in solid tumors and in the retina of patients with diabetes. This vascularization results in the growth and spread of tumor cells and blind-ness, respectively. By targeting the VEGF receptors and the Notch pathway involved in regulating them, re-searchers are seeking ways to block angiogenesis and prevent cancer cells or the retina from becoming vascu-larized (Miller et al. 2013; Wilson et al. 2013).

Literature Cited

Ambati, B. K. and 36 others. 2006. Corneal avascularity is due to soluble VEGF receptor-1. Nature 443: 993–997.
PubMed Link

Levine, R. J. and 12 others. 2006. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. New Engl. J. Med. 355: 992–1005.
PubMed Link

Miller, J. W., J. Le Couter, E. C. Strauss and N. Ferrara. 2013. Vascular endothelial growth factor a in intra-ocular vascular disease. Ophthalmology 120: 106–114. 
PubMed Link

Mutter, W. P. and S. A. Karumanchi. 2008. Molecular mechanisms of preeclampsia. Microvasc. Res. 75: 1–8.
PubMed Link

Seo, S., H. P. Singh, P. M. Lacal, A. Sasman, A. Fatima, T. Liu, K. M. Schultz, D. W. Losordo, O. J. Lehmann and T. Kume. 2012.  Forkhead box transcription factor FoxC1 preserves corneal transparency by regulat-ing vascular growth. Proc. Natl. Acad. Sci. USA 109: 2015–2020.
PubMed Link

Wilson, P. M., M. J. LaBonte and H. J. Lenz. 2013. Assessing the in vivo efficacy of biologic antiangiogenic therapies. Cancer Chemother. Pharmacol. 71: 1–12.
PubMed Link

1 The manatee is the only mammal known to have a vascularized cornea, and it turns out that this exception proves the rule—the cornea of the manatee does not express the soluble VEGF receptor. The manatee’s closest relatives (dugongs and elephants) do express it, and their corneas are avascular (Ambati et al. 2006). This morphological distinction among related taxa provides further evidence of the im-portance of soluble VEGF in preventing corneal vascularization.

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