Inhibition of Jagged-Specific Notch Activation Reduces Luteal Angiogenesis and Causes Luteal Hemorrhaging of Hormonally Stimulated Ovaries

Abstract

Robust angiogenesis in the corpus luteum is critical for maintenance of pregnancy and thus mammalian female fertility. During angiogenesis, blood vessels sprout from pre-existing vasculature and recruit pericytes to induce maturation and vessel quiescence. Pericytes are associated with capillaries and regulate endothelial cell proliferation, vessel diameter, and vascular permeability. Endothelial induction of Notch signaling in adjacent pericytes helps recruit and maintain pericyte coverage in some but not all tissue types. We have employed a Notch decoy, N1 10−24 , which blocks Notch signaling in a ligand-specific manner, and determined that pharmacological inhibition of Notch ligand Jagged blocks luteal angiogenesis after normal ovulation, resulting in reduced luteal vasculature. Conversely, after ovarian hyperstimulation, a condition which occurs during fertility treatments, Jagged inhibition causes vascular dilation and hemorrhage. These results indicate that Jagged inhibition has effects in different ovarian angiogenic conditions, promoting vascular growth in the corpus luteum and vascular stability in hyperstimulated ovaries.

Defining the cellular complexity of the zebrafish bipotential gonad

“…The copyright holder for this preprint this version posted January 20, 2023. ; https://doi.org/10.1101/2023.01.18.524593 doi: bioRxiv preprint that pericytes are essential for vascular stability and reconstruction of the ovarian vasculature during follicle development and post-ovulation (65)(66)(67)(68). Consistent with this finding, inhibition of PDGFR in the rat ovary causes hemorrhaging (69).…”

“…In embryonic zebrafish, pdgfrb is required for the formation of the intersegmental vessels and meningeal angiogenesis (63,64). In other species, it is known that pericytes are essential for vascular stability and reconstruction of the ovarian vasculature during follicle development and post-ovulation (65–68). Consistent with this finding, inhibition of PDGFR in the rat ovary causes hemorrhaging (69).…”

Defining the cellular complexity of the zebrafish bipotential gonad

“…In embryonic zebrafish, pdgfrb is required for the formation of the intersegmental vessels and meningeal angiogenesis [72, 73]. In other species, it is known that pericytes are essential for vascular stability and reconstruction of the ovarian vasculature during follicle development and post-ovulation [74–77]. Consistent with this finding, inhibition of Pdgfrb in the rat ovary causes hemorrhaging [78].…”

Innovation and Discovery in Cardiovascular Biology

“…Two exciting research articles focus their efforts on therapeutically targeting the vascular system. Kofler et al 6 capitalize on the robust physiological angiogenesis associated with corpus luteal formation following ovulation to test and characterize the effects of Jagged-specific Notch inhibition on vascular growth and pericyte recruitment. Their studies reveal remarkable differences between the vascular effects of Notch inhibition during normal ovulation compared to hyperstimulated ovulationa condition that is present in women undergoing assisted reproductive technologies.…”