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(Circulation. 2005;111:1826-1832.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Essential Role of Endothelial Notch1 in Angiogenesis

Florian P. Limbourg, MD^*; Kyosuke Takeshita, MD, PhD^*; Freddy Radtke, PhD; Roderick T. Bronson, DVM; Michael T. Chin, MD, PhD; James K. Liao, MD

From the Vascular Medicine Research Unit (F.P.L., K.T., M.T.C., J.K.L.), Brigham & Women’s Hospital and Harvard Medical School, Boston, Mass; Ludwig Institute for Cancer Research (F.R.), Epalinges, Switzerland; and Rodent Histopathology Core (R.T.B.), Harvard Medical School, Boston, Mass.

Correspondence to James K. Liao, Brigham & Women’s Hospital, 65 Landsdowne St, Room 275, Cambridge, MA 02139. E-mail jliao{at}rics.bwh.harvard.edu

Received August 9, 2004; revision received December 2, 2004; accepted December 8, 2004.

Background— Notch signaling influences binary cell fate decisions in a variety of tissues. The Notch1 receptor is widely expressed during embryogenesis and is essential for embryonic development. Loss of global Notch1 function results in early embryonic lethality, but the cell type responsible for this defect is not known. Here, we identify the endothelium as the primary target tissue affected by Notch1 signaling.

Methods and Results— We generated an endothelium-specific deletion of Notch1 using Tie2Cre and conditional Notch1^flox/flox mice. Mutant embryos lacking endothelial Notch1 died at approximately embryonic day 10.5 with profound vascular defects in placenta, yolk sac, and embryo proper, whereas heterozygous deletion had no effect. In yolk sacs of mutant embryos, endothelial cells formed a primary vascular plexus indicative of intact vasculogenesis but failed to induce the secondary vascular remodeling required to form a mature network of well-organized large and small blood vessels, which demonstrates a defect in angiogenesis. These vascular defects were also evident in the placenta, where blood vessels failed to invade the placental labyrinth, and in the embryo proper, where defective blood vessel maturation led to pericardial and intersomitic hemorrhage. Enhanced activation of caspase-3 was detected in endothelial and neural cells of mutant mice, which resulted in enhanced apoptotic degeneration of somites and the neural tube.

Conclusions— These findings recapitulate the vascular phenotype of global Notch1^–/– mutants and indicate an essential cell-autonomous role of Notch1 signaling in the endothelium during vascular development. These results may have important clinical implications with regard to Notch1 signaling in adult angiogenesis.

Key Words: vasculature • genetics • defects • angiogenesis • endothelium

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