Rapid growth of a network of blood vessels in the uterus and placenta upon implantation of the mammalian embryo is required for the exchange of nutrients and waste products between the mother and the fetus. The formation of the vasculature at this site presents several critical regulatory problems, which will be explored in the mouse. Unlike other vessels, uterine vessels that reach the placenta do not reseal at the growing end, but instead release blood into pools called blood sinuses; placental cells directly contact the maternal blood in these sinuses, enabling an efficient exchange of metabolites and gasses and the rapid distribution of placental-hormones throughout the maternal bloodstream. Another unusual feature is that vessel growth is prevented through the outer layers of the placenta; if vessels from the mother and fetus did not cross these layers, two consequences would be the exposure of the fetus to maternal immune cells (which would attack the fetus as foreign) and extensive (possibly fatal) vessel rupture and hemorrhaging at birth. our recent results suggest that we have discovered two of the key regulators of uterine-placental neovascularization in the mouse, proliferin and proliferin-related protein, which are both members of the prolactin/growth hormone family of protein hormones and are, respectively, major positive and negative regulators of blood vessel growth (angiogenesis) secreted by the placenta. This discovery makes several predictions about how the unique aspects of angiogenesis at the implantation site are regulated. Proposed experiments, using transgenic and targeted gene disruption mouse models, will test the hypothesize physiological roles of proliferin- related protein in the temporal and spatial restriction of vessel growth. Other studies will investigate the signal transduction pathways through which proliferin induces, and proliferin-related protein inhibits, angiogenesis. This research has direct implications for the management and treatment of infertility and pregnancy-related disorders, but may also provide novel insights into the process of vascularization to human disease, for example in cancer.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD024518-12
Application #
6181565
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Ilekis, John V
Project Start
1988-08-01
Project End
2003-05-31
Budget Start
2000-06-01
Budget End
2001-05-31
Support Year
12
Fiscal Year
2000
Total Cost
$223,267
Indirect Cost
Name
Northwestern University at Chicago
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
City
Evanston
State
IL
Country
United States
Zip Code
60201
Bhattacharyya, Sumit; Lin, Jiandie; Linzer, Daniel I H (2002) Reactivation of a hematopoietic endocrine program of pregnancy contributes to recovery from thrombocytopenia. Mol Endocrinol 16:1386-93
Zhou, Beiyan; Lum, Hillary E; Lin, Jiandie et al. (2002) Two placental hormones are agonists in stimulating megakaryocyte growth and differentiation. Endocrinology 143:4281-6
Toft, D J; Rosenberg, S B; Bergers, G et al. (2001) Reactivation of proliferin gene expression is associated with increased angiogenesis in a cell culture model of fibrosarcoma tumor progression. Proc Natl Acad Sci U S A 98:13055-9
Lefebvre, P; Lin, J; Linzer, D I et al. (2001) Murine prolactin-like protein E synergizes with human thrombopoietin to stimulate expansion of human megakaryocytes and their precursors. Exp Hematol 29:51-8
Lin, J; Toft, D J; Bengtson, N W et al. (2000) Placental prolactins and the physiology of pregnancy. Recent Prog Horm Res 55:37-51; discussion 52
Bengtson, N W; Linzer, D I (2000) Inhibition of tumor growth by the antiangiogenic placental hormone, proliferin-related protein. Mol Endocrinol 14:1934-43
Toft, D J; Linzer, D I (2000) Identification of three prolactin-related hormones as markers of invasive trophoblasts in the rat. Biol Reprod 63:519-25
Lin, J; Linzer, D I (1999) A novel megakaryocyte differentiation factor from mouse placenta. Trends Cardiovasc Med 9:167-71
Lin, J; Linzer, D I (1999) Induction of megakaryocyte differentiation by a novel pregnancy-specific hormone. J Biol Chem 274:21485-9
Toft, D J; Linzer, D I (1999) Prolactin (PRL)-like protein J, a novel member of the PRL/growth hormone family, is exclusively expressed in maternal decidua. Endocrinology 140:5095-101

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