Much remains to be learned about the periodic menstrual sloughing, bleeding and regenerative repair process so characteristic of the primate endometrium. During the previous research period, the investigator discovered an unexpected involvement of vascular endothelial growth factor (VEGF) and its receptors (R) in the menstrual inductive process. Very early in the premenstrual phase, one of the VEGF receptors, VEGFR-2, also known as KDR, was strongly expressed in the stromal cells (not the vascular endothelium) of the upper endometrial zones, the same cell population that expresses most of the matrix metalloproteinases (MMPs). MMPs are enzymes responsible for the tissue destruction and sloughing associated with menstruation. FLT-1, another VEGF receptor, was also transiently upregulated in the glandular cells which also produce an MMP, called matrilysin. Therefore the investigators hypothesize that VEGF acts through KDR and FLT-1 to facilitate MMP expression in the upper endometrial zones during menstrual induction. Hepatocyte growth factor (HGF) was also expressed transiently in the same endometrial stromal cells at the same time. The investigators hypothesize that HGF and VEGF may interact during the LFT to facilitate MMP upregulation. Keratinocyte growth factor (KGF), a growth factor strongly upregulated by P, had strong trophic effects on the spiral arteries, but the KGF receptor was not detectable in the arteries. The arteries do express KDR and FLT-1, so they hypothesize that KGF acts indirectly through the VEGF system to mediate spiral artery growth under P influence. In the current application they propose to explore the interactions between VEGF, HGF and KGF in the primate endometrium within the following specific aims: 1. The VEGF family and MMPs during menstrual induction. 2. VEFG-HGF interactions in MMP regulation. 3. KGF-VEGF interactions in spiral artery growth. 4. HGF and VEGF antagonists during menstruation.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD019182-15
Application #
6127029
Study Section
Reproductive Biology Study Section (REB)
Program Officer
Yoshinaga, Koji
Project Start
1984-09-01
Project End
2005-04-30
Budget Start
2000-05-22
Budget End
2001-04-30
Support Year
15
Fiscal Year
2000
Total Cost
$344,475
Indirect Cost
Name
Oregon Health and Science University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
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Slayden, Ov D; Brenner, Robert M (2006) A critical period of progesterone withdrawal precedes menstruation in macaques. Reprod Biol Endocrinol 4 Suppl 1:S6
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Lindsey, J Suzanne; Brenner, Robert M (2002) Novel hepatocyte growth factor/scatter factor isoform transcripts in the macaque endometrium and placenta. Mol Hum Reprod 8:81-7

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