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.
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