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Theses Doctoral

Notch deficiency leads to arteriovenous malformations and altered pericyte function

Kolfer, Natalie

During angiogenesis, nascent blood vessels sprout from pre-existing vasculature and recruit pericytes to induce maturation and vessel quiescence. Perictyes are associated with small vessels and capillaries where they share the basement membrane with the endothelium to provide vascular support. Pericytes are a critical component of the blood-brain barrier and regulate endothelial cell proliferation, vessel diameter, and vascular permeability. Endothelial cells express Notch1, whereas pericytes express both Notch1 and Notch3. Here we show that Notch signaling is essential for pericyte function. Through genetic manipulation and pharmacological tools we show that Notch regulates pericyte recruitment and pericyte/endothelial cell interactions. Notch1^+/-;Notch3^-/- mutant mice display decreased pericyte coverage and altered pericyte association with the retinal vascular plexus. Notch deficiency is associated with vascular anomalies where Notch1^+/-;Notch3-/- mice display retinal arteriovenous malformations (AVM) characterized by dilated vessels, vascular tangles and arteriovenous shunts that are similar to human brain AVMs. Disruption of pericyte/endothelial cell association is accompanied by an increase in vascular density, venule enlargement, and increased vascular permeability observed prior to AVM formation. In the ovary, we show that Jagged is essential for pericyte association with the endothelium where inhibition of Jagged-specific Notch activation results in luteal vessel dilation and hemorrhaging following ovarian hyperstimulation. By in vitro analysis of cultured pericytes we show that Notch1 and Notch3 induce plated derived growth factor receptor-β (PDGFR-β) expression to regulate cell migration. These findings expand the role for Notch in angiogenesis by demonstrating that Notch signaling in pericytes is essential for vascular development and function.

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More About This Work

Academic Units
Cellular, Molecular and Biomedical Studies
Thesis Advisors
Kitajewski, Jan
Degree
Ph.D., Columbia University
Published Here
May 22, 2013
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