Conclusions

In summary, recent advances have uncovered the unexpected finding that specialized fetal cells of the human placenta—CTBs—undergo a novel pseudovasculogenesis differentiation program that enables them to masquerade as the endothelial lining of maternal uterine vessels. Discovery of the regulatory mechanisms that govern this unusual transformation is offering fascinating insights into how the placenta forms. Will the results of these studies be applicable to other normal and pathogenic processes that require similar sorts of plasticity? Probably. It is now clear that some tumor cells also mimic the properties of vascular cells (reviewed in Ref. [13]), an important consideration for the design of antiangiogenesis cancer therapies. Whether or not elements of the strategy used by CTBs to remodel the uter

Figure 3 In pre-eclampsia, staining of invasive cytotrophoblasts with anti-VEGF-A decreased. In the third trimester of normal pregnancy (38 wk), cytotrophoblasts (CTB) in the interstitium (arrow) and in the walls of blood vessels (BV) (arrowheads) stained for VEGF-A (B). In pre-eclampsia (PE), staining of invasive cytotrophoblasts for VEGF-A was strikingly downregulated (D, F). CK, cytokeratin staining to identify trophoblasts; VS, villus stroma. (Reproduced with permission from the American Journal of Pathology.)

Figure 3 In pre-eclampsia, staining of invasive cytotrophoblasts with anti-VEGF-A decreased. In the third trimester of normal pregnancy (38 wk), cytotrophoblasts (CTB) in the interstitium (arrow) and in the walls of blood vessels (BV) (arrowheads) stained for VEGF-A (B). In pre-eclampsia (PE), staining of invasive cytotrophoblasts for VEGF-A was strikingly downregulated (D, F). CK, cytokeratin staining to identify trophoblasts; VS, villus stroma. (Reproduced with permission from the American Journal of Pathology.)

ine vasculature could be exploited for therapeutic angiogen-esis of ischemic conditions is an interesting question that has yet to be addressed.

Glossary

Cytotrophoblasts: The specialized epithelial cells of the placenta.

Placenta: A transient organ that supplies food and oxygen to the fetus.

Pseudovasculogenesis: The ability to partially imitate cells that line blood vessels.

Vascular mimicry: The ability to imitate cells that line blood vessels.

Acknowledgment

Supported by HL 64597 and HD 30367.

Further Reading

1. Norwitz, E. R., Schust, D. J., and Fisher, S. J. (2001). Implantation and the survival of early pregnancy. N. Engl. J. Med. 345, 1400-1408.

2. Paria, B. C., Reese, J., Das, S. K., and Dey, S. K. (2002). Deciphering the cross-talk of implantation: Advances and challenges. Science 296, 2185-2188.

3. Damsky, C. H., and Fisher, S. J. (1998). Trophoblast pseudo-vasculogenesis: Faking it with endothelial adhesion receptors. Curr. Opin. Cell Biol. 10, 660-666. This article is a review of the process whereby cytotrophoblasts switch their adhesion molecule phenotype to resemble that of endothelial cells.

4. Zhou, Y., McMaster, M., Woo, K., Janatpour, M., Perry, J., Karpanen, T., Alitalo, K., Damsky, C., and Fisher, S. J. (2002). Vascular endothe-lial growth factor ligands and receptors that regulate human cytotro-phoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am. J. Pathol. 160, 1405-1423.

5. Zhou, Y., Bellingard-Dubouchaud, V., Feng, K.-T., McMaster, M., and Fisher, S. J. (YEAR). Human cytotrophoblasts promote endothelial survival and vascular remodeling through secretion of Ang-2, PlGF, and VEGF-C. Dev. Biol. (in press).

6. Genbacev, O., Joslin, R., Damsky, C. H., Polliotti, B. M., and Fisher, S. J. (1996). Hypoxia alters early gestation human cytotrophoblast differentiation/invasion in vitro and models the placental defects that occur in preeclampsia. J. Clin. Invest. 97, 540-550.

7. Genbacev, O., Zhou, Y., Ludlow, J. W., and Fisher, S. J. (1997). Regulation of human placental development by oxygen tension. Science

277, 1669-1672. This article describes a role for physiological hypoxia in regulating human placental development.

8. Genbacev, O., Krtolica, A., Kaelin, W., and Fisher, S. J. (2001). Human cytotrophoblast expression of the von Hippel-Lindau protein is down-regulated during uterine invasion in situ and upregulated by hypoxia in vitro. Dev. Biol. 233, 526-536.

9. Roberts, J. M., and Lain, K. Y. (2002). Recent insights into the pathogenesis of pre-eclampsia. Placenta 23, 359-372.

10. Brosens, I. A., Robertson, W. B., and Dixon, H. G. (1972). The role of the spiral arteries in the pathogenesis of preeclampsia. Obstet. Gynecol. Annu. 1, 177-191.

11. Zhou, Y., Damsky, C. H., and Fisher, S. J. (1997). Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome? J. Clin. Invest. 99, 2152-2164. This article shows that pre-eclampsia is associated with defects in the cytotrophoblast pseudovasculogenesis program.

12. Maynard, S. E., Min, J. Y., Merchan, J., Lim, K. H., Li, J., Mondal, S., Libermann, T. A., Morgan, J. P., Sellke, F. W., Stillman, I. E., Epstein, F. H., Sukhatme, V. P., and Karumanchi, S. A. (2003). Excess placental soluble fms-like tyrosine kinase 1 (sFltl) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J. Clin. Invest. 111, 649-658.

13. Hendrix, M. J., Seftor, E. A., Hess, A. R., and Seftor, R. E. (2003). Vas-culogenic mimicry and tumour-cell plasticity: Lessons from melanoma. Nat. Rev. Cancer 3, 411-421.

Capsule Biography

Susan Fisher's laboratory at the University of California-San Francisco has studied human placental development for two decades. In addition to the work described here, the group also examines mechanisms of implantation and maternal tolerance of the fetal hemi-allograft.

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