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.

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. 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.

García-Pascual CM ，Zimmermann RC ，Ferrero H ，Shawber CJ ，Kitajewski J ，Simón C ，Pellicer A ，Gómez R ... -  《-》

Synaptojanin-2 binding protein stabilizes the Notch ligands DLL1 and DLL4 and inhibits sprouting angiogenesis.

Adam MG ，Berger C ，Feldner A ，Yang WJ ，Wüstehube-Lausch J ，Herberich SE ，Pinder M ，Gesierich S ，Hammes HP ，Augustin HG ，Fischer A ... -  《-》

Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis.

Hellström M ，Phng LK ，Hofmann JJ ，Wallgard E ，Coultas L ，Lindblom P ，Alva J ，Nilsson AK ，Karlsson L ，Gaiano N ，Yoon K ，Rossant J ，Iruela-Arispe ML ，Kalén M ，Gerhardt H ，Betsholtz C ... -  《-》

Inhibition of Delta-like 4 mediated signaling induces abortion in mice due to deregulation of decidual angiogenesis.

To explore whether the Dll4/Notch1 pathway plays a key role in regulating the vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) driven decidual angiogenesis and related pregnancy through induction of a tip/stalk phenotype. Progesterone-replaced ovariectomized pregnant mice received a single injection of YW152F (Dll4 blocking antibody, BAb) or placebo at embryonic day (E) 4.5. Animals were sacrificed at different time points; blood and uterus were collected for further analysis. Number of embryos and implantation site, uteri weight, and serum progesterone levels were assessed. Alterations in the tip/stalk phenotype were determined by quantitative immunofluorescent analysis of vascularization, Dll4 expression, cellular proliferation and apoptosis in uterine sections. Abrogation of Dll4 signaling leads to a promiscuous expression of Dll4, increased cell proliferation, apoptosis and vascularization at E 6.5. Such an abrogation was associated with a dramatic disruption of embryo growth and development starting at E 9.5. The observed promiscuous expression of Dll4 and the increase in cell proliferation, apoptosis and vascularization are events compatible with loss of the tip/stalk phenotype. Excessive (although very likely defective) decidual angiogenesis due to such vascular alterations is the most likely cause of subsequent interruption of embryo development and related pregnancy in Dll4 treated mice. Dll4 plays a key role in regulating decidual angiogenesis and related pregnancy through induction of a tip/stalk phenotype.

García-Pascual CM ，Ferrero H ，Zimmermann RC ，Simón C ，Pellicer A ，Gómez R ... -  《-》

The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching.

Suchting S ，Freitas C ，le Noble F ，Benedito R ，Bréant C ，Duarte A ，Eichmann A ... -  《-》