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Inhibition of delta-like ligand 4 induces luteal hypervascularization followed by functional and structural luteolysis in the primate ovary.
- Source :
-
Endocrinology [Endocrinology] 2012 Apr; Vol. 153 (4), pp. 1972-83. Date of Electronic Publication: 2012 Feb 14. - Publication Year :
- 2012
-
Abstract
- Using specific inhibitors established that angiogenesis in the ovarian follicle and corpus luteum is driven by vascular endothelial growth factor. Recently, it has been demonstrated that the Notch ligand, delta-like ligand 4 (Dll4) negatively regulates vascular endothelial growth factor-mediated vessel sprouting and branching. To investigate the role of Dll4 in regulation of the ovarian vasculature, we administered a neutralizing antibody to Dll4 to marmosets at the periovulatory period. The vasculature was examined on luteal d 3 or d 10: angiogenesis was determined by incorporation of bromodeoxyuridine, staining for CD31 and cell death by staining for activated caspase-3. Ovulatory progesterone rises were monitored to determine effects of treatment on luteal function and time to recover normal cycles in a separate group of animals. Additionally, animals were treated in the follicular or midluteal phase to determine effects of Dll4 inhibition on follicular development and luteal function. Controls were treated with human IgG (Fc). Corpora lutea from marmosets treated during the periovulatory period exhibited increased angiogenesis and increased vascular density on luteal d 3, but plasma progesterone was significantly suppressed. By luteal d 10, corpora lutea in treated ovaries were significantly reduced in size, with involution of luteal cells, increased cell death, and suppressed plasma progesterone concentrations. In contrast, initiation of anti-Dll4 treatment during the midluteal phase produced only a slight suppression of progesterone for the remainder of the cycle. Moreover, Dll4 inhibition had no appreciable effect on follicular development. These results show that Dll4 has a specific and critical role in the development of the normal luteal vasculature.
- Subjects :
- Animals
Antibodies, Neutralizing pharmacology
Apoptosis physiology
Corpus Luteum drug effects
Corpus Luteum pathology
Female
Immunoglobulin G pharmacology
Intracellular Signaling Peptides and Proteins drug effects
Intracellular Signaling Peptides and Proteins physiology
Membrane Proteins drug effects
Membrane Proteins physiology
Models, Animal
Neovascularization, Physiologic drug effects
Platelet Endothelial Cell Adhesion Molecule-1 metabolism
Progesterone blood
Receptors, Notch metabolism
Vascular Endothelial Growth Factor A physiology
Callithrix physiology
Corpus Luteum blood supply
Intracellular Signaling Peptides and Proteins antagonists & inhibitors
Luteolysis physiology
Membrane Proteins antagonists & inhibitors
Neovascularization, Physiologic physiology
Ovary physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1945-7170
- Volume :
- 153
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Endocrinology
- Publication Type :
- Academic Journal
- Accession number :
- 22334711
- Full Text :
- https://doi.org/10.1210/en.2011-1688