Delta like ligand 4 regulates vascular endothelial growth factor receptor 2 driven luteal angiogenesis through induction of a tip stalk phenotype in proliferating endothelial cells

Blockade of Dll4 in an in vivo rodent model shows that VEGFR2-mediated sprouting during luteal angiogenesis is modulated by the Dll4/Notch-1 pathway, which induces a tip/stalk phenotype.


Carmen M. García-Pascual, Ph.D., Ralf C. Zimmermann, M.D., Hortensia Ferrero, Ph.D., Carrie Shawber, Ph.D., Jan Kitajewski, Ph.D., Carlos Simón, M.D., Antonio Pellicer, M.D., Raúl Gómez, Ph.D.

Volume 100, Issue 6, Pages 1768-1776.e1, December 2013



To explore whether the Dll4/Notch-1 signaling pathway modulates vascular endothelial growth factor (VEGF)-dependent luteal angiogenesis and related function, by inducing a tip/stalk phenotype in endothelial cells (ECs).


Experimental laboratory animal study.


University-affiliated infertility center.


Immature female mice.


The presence of leading tip ECs in growing luteal vessel was identified by immunofluorescent analysis of Dll4 in the ovaries of hormonally stimulated female mice. The effects of Dll4 inhibition on luteal vessels functionality and related corpus luteum function were assessed by administering a Dll4 blocking antibody or placebo to hormonally stimulated female mice.

Main Outcome Measure(s):

Alteration of the tip/stalk phenotype was identified by immunofluorescence analysis of luteal vascular density, Dll4, Notch-1, and VEGF receptor 2 expression. Lectin perfusion was used to assay blood vessel functionality, whereas apoptosis and P levels were quantified to determine the effects on luteal function.


Expression of Dll4 was restricted to the tip of growing vessels. Inhibition of Dll4 signaling promotes promiscuous Dll4 expression, leading to increased, but paradoxically, nonfunctional vascularization, which was associated with decreased P levels.


The Dll4/Notch-1 signaling pathway has a modulatory role in VEGF-dependent luteal angiogenesis and related function through induction of a tip/stalk phenotype.

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