The long-term objective of the project is to determine the cellular mechanisms involved in the migration of extravillous trophoblast cells into the maternal spiral arteries and their role in the modification of the arterial wall. Adequate invasion and modification of the arteries appears necessary to provide a normal blood supply to the placenta. Inadequate invasion and remodeling has been associated with pregnancies complicated by hypertension and intrauterine growth retardation and has been suggested as a cause of miscarriages. Because of limitations associated with acquisition of human material at precise developmental ages, and the fact that this type of invasion occurs only in higher primates, we have used the macaque animal model to explore the cellular biology of this phenomenon. In the present application three specific aims are proposed that will explore three related hypotheses: I) that trophoblast cells utilize a system of cell-cell adhesion molecules to migrate along the maternal endothelium. Whereas much has been learned about leukocyte and tumor cell adhesion to endothelial cells, little is known regarding trophoblast-endothelial interactions. We will examine the molecular basis of this interaction by a combination of immunocytochemical localizations to determine what adhesion molecules are present in situ and verify their functional involvement using an in vitro cell adhesion assay. 2) that trophoblast utilizes the extracellular matrix (ECM) and a family of matrix receptors (integrins) as a means to invade the walls of the arteries. Once trophoblast cells have migrated along the artery to some depth, they then extravasate and invade the wall of the artery, disrupting the muscular and ECM components. In the process of accomplishing this, we hypothesize that the cells interact with ECM components in the basement membrane and elsewhere, using these interactions as a basis for adhesion or migration. We will determine the types of ECM present in the arterial wall, how these change in response to invasion, and how integrin expression is modulated as cells invade the arterial wall. Together, the results of these two specific aims should provide significant new insights as to the molecular mechanisms utilized by trophoblast to accomplish this physiologically important process. Finally, 3) we hypothesize that trophoblast cells in the walls of the spiral arteries remain functionally active and may be the source of vasoactive substances that could act locally or regionally to regulate maternal blood flow to the placenta. Our preliminary studies have shown the presence of immunoreactive endothelin- 1, a potent vasoconstrictor, and calcitonin gene-related peptide, a potent vasodilator, in many trophoblast cells in the walls of the spiral arteries. Experiments outlined in this proposal will confirm and extend these observations. The macaque is an excellent animal in which to explore this hypothesis and our findings should add significant new information on potential factors regulating the maternal blood supply to the placenta.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD024491-05
Application #
2199194
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1988-03-01
Project End
1998-08-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
5
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of California Davis
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Enders, A C; Blankenship, T N (2012) Interstitial trophoblast cells: an enigmatic and variable component of the developing macaque placenta. Placenta 33:672-6
Enders, A C (2007) Implantation in the macaque: expansion of the implantation site during the first week of implantation. Placenta 28:794-802
Enders, A C; Blankenship, T N; Fazleabas, A T et al. (2001) Structure of anchoring villi and the trophoblastic shell in the human, baboon and macaque placenta. Placenta 22:284-303
Enders, A C (2000) Trophoblast-uterine interactions in the first days of implantation: models for the study of implantation events in the human. Semin Reprod Med 18:255-63
Douglas, G C; Thirkill, T L; Blankenship, T N (1999) Vitronectin receptors are expressed by macaque trophoblast cells and play a role in migration and adhesion to endothelium. Biochim Biophys Acta 1452:36-45
Blankenship, T N; Enders, A C (1997) Trophoblast cell-mediated modifications to uterine spiral arteries during early gestation in the macaque. Acta Anat (Basel) 158:227-36
Enders, A C; Blankenship, T N (1997) Modification of endometrial arteries during invasion by cytotrophoblast cells in the pregnant macaque. Acta Anat (Basel) 159:169-93
King, B F; Blankenship, T N (1997) Immunohistochemical localization of fibrillin in developing macaque and term human placentas and fetal membranes. Microsc Res Tech 38:42-51
Blankenship, T N; Enders, A C (1997) Expression of platelet-endothelial cell adhesion molecule-1 (PECAM) by macaque trophoblast cells during invasion of the spiral arteries. Anat Rec 247:413-9
Blankenship, T N; King, B F (1996) Macaque intra-arterial trophoblast and extravillous trophoblast of the cell columns and cytotrophoblastic shell express neural cell adhesion molecule (NCAM). Anat Rec 245:525-31

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