TY - JOUR
T1 - Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression
AU - Shawber, Carrie J.
AU - Funahashi, Yasuhiro
AU - Francisco, Esther
AU - Vorontchikhina, Marina
AU - Kitamura, Yukari
AU - Stowell, Stephanie A.
AU - Borisenko, Valeriya
AU - Feirt, Nikki
AU - Podgrabinska, Simona
AU - Shiraishi, Kazuko
AU - Chawengsaksophak, Kallayanee
AU - Rossant, Janet
AU - Accili, Domenico
AU - Skobe, Mihaela
AU - Kitajewski, Jan
PY - 2007/11/1
Y1 - 2007/11/1
N2 - The Notch family of cell surface receptors and its ligands are highly conserved proteins that regulate cell fate determination, including those involved in mammalian vascular development. We report that Notch induces VEGFR-3 expression in vitro in human endothelial cells and in vivo in mice. In vitro, Notch in complex with the DNA-binding protein CBF-1/suppressor of hairless/Lag1 (CSL) bound the VEGFR-3 promoter and transactivated VEGFR-3 specifically in endothelial cells. Through induction of VEGFR-3, Notch increased endothelial cell responsiveness to VEGF-C, promoting endothelial cell survival and morphological changes. In vivo, VEGFR-3 was upregulated in endothelial cells with active Notch signaling. Mice heterozygous for null alleles of both Notch1 and VEGFR-3 had significantly reduced viability and displayed midgestational vascular patterning defects analogous to Notch1 nullizygous embryos. We found that Notch1 and Notch4 were expressed in normal and tumor lymphatic endothelial cells and that Notch1 was activated in lymphatic endothelium of invasive mammary micropapillary carcinomas. These results demonstrate that Notch1 and VEGFR-3 interact genetically, that Notch directly induces VEGFR-3 in blood endothelial cells to regulate vascular development, and that Notch may function in tumor lymphangiogenesis.
AB - The Notch family of cell surface receptors and its ligands are highly conserved proteins that regulate cell fate determination, including those involved in mammalian vascular development. We report that Notch induces VEGFR-3 expression in vitro in human endothelial cells and in vivo in mice. In vitro, Notch in complex with the DNA-binding protein CBF-1/suppressor of hairless/Lag1 (CSL) bound the VEGFR-3 promoter and transactivated VEGFR-3 specifically in endothelial cells. Through induction of VEGFR-3, Notch increased endothelial cell responsiveness to VEGF-C, promoting endothelial cell survival and morphological changes. In vivo, VEGFR-3 was upregulated in endothelial cells with active Notch signaling. Mice heterozygous for null alleles of both Notch1 and VEGFR-3 had significantly reduced viability and displayed midgestational vascular patterning defects analogous to Notch1 nullizygous embryos. We found that Notch1 and Notch4 were expressed in normal and tumor lymphatic endothelial cells and that Notch1 was activated in lymphatic endothelium of invasive mammary micropapillary carcinomas. These results demonstrate that Notch1 and VEGFR-3 interact genetically, that Notch directly induces VEGFR-3 in blood endothelial cells to regulate vascular development, and that Notch may function in tumor lymphangiogenesis.
UR - http://www.scopus.com/inward/record.url?scp=36048978608&partnerID=8YFLogxK
U2 - 10.1172/JCI24311
DO - 10.1172/JCI24311
M3 - Article
C2 - 17948123
AN - SCOPUS:36048978608
SN - 0021-9738
VL - 117
SP - 3369
EP - 3382
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 11
ER -