Combined deficiency of Notch1 and Notch3 causes pericyte dysfunction, models CADASIL, and results in arteriovenous malformations

Pericytes regulate vessel stability and pericyte dysfunction contributes to retinopathies, stroke, and cancer. Here we define Notch as a key regulator of pericyte function during angiogenesis. In Notch1(+/-); Notch3(-/-) mice, combined deficiency of Notch1 and Notch3 altered pericyte interaction with the endothelium and reduced pericyte coverage of the retinal vasculature. Notch1 and Notch3 were shown to cooperate to promote proper vascular basement membrane formation and contribute to endothelial cell quiescence. Accordingly, loss of pericyte function due to Notch deficiency exacerbates endothelial cell activation caused by Notch1 haploinsufficiency. Mice mutant for Notch1 and Notch3 develop arteriovenous malformations and display hallmarks of the ischemic stroke disease CADASIL. Thus, Notch deficiency compromises pericyte function and contributes to vascular pathologies.Peer reviewe

NOTCH Decoys That Selectively Block DLL/NOTCH or JAG/NOTCH Disrupt Angiogenesis by Unique Mechanisms to Inhibit Tumor Growth

A pro-angiogenic role for Jagged-dependent activation of Notch signaling in the endothelium has yet to be described. Using proteins that encoded different NOTCH1 EGF-like repeats, we identified unique regions of DLL-class and JAG-class ligand/receptor interactions, and developed Notch decoys that function as ligand-specific Notch inhibitors. N1(10-24) decoy blocked JAG1/JAG2-mediated NOTCH1 signaling, angiogenic sprouting in vitro and retinal angiogenesis, demonstrating JAG-dependent Notch signal activation promotes angiogenesis. In tumors, N1(10-24) decoy reduced angiogenic sprouting, vessel perfusion, pericyte coverage, and tumor growth. JAG/NOTCH signaling uniquely inhibited expression of anti-angiogenic sVEFGFR-1/sFlt-1. N1(1-13) decoy interfered with DLL1/DLL4-mediated NOTCH1 signaling and caused endothelial hypersprouting in vitro, in retinal angiogenesis and in tumors. Thus, blockade of JAG- or DLL-mediated Notch signaling inhibits angiogenesis by distinct mechanisms. JAG/Notch signaling positively regulates angiogenesis by suppressing sVEGFR-1/sFlt-1 and promoting mural/endothelial cell interactions. Blockade of JAG-class ligands represents a novel, viable therapeutic approach to block tumor angiogenesis and growth

Endothelial Jagged-1 Is Necessary for Homeostatic and Regenerative Hematopoiesis

The bone marrow (BM) microenvironment is composed of multiple niche cells that, by producing paracrine factors, maintain and regenerate the hematopoietic stem cell (HSC) pool (Morrison and Spradling, 2008). We have previously demonstrated that endothelial cells support the proper regeneration of the hematopoietic system following myeloablation (Butler et al., 2010; Hooper et al., 2009; Kobayashi et al., 2010). Here, we demonstrate that expression of the angiocrine factor Jagged-1, supplied by the BM vascular niche, regulates homeostatic and regenerative hematopoiesis through a Notch-dependent mechanism. Conditional deletion of Jagged-1 in endothelial cells (Jag1(ECKO) mice) results in a profound decrease in hematopoiesis and premature exhaustion of the adult HSC pool, whereas quantification and functional assays demonstrate that loss of Jagged-1 does not perturb vascular or mesenchymal compartments. Taken together, these data demonstrate that the instructive function of endothelial-specific Jagged-1 is required to support the self-renewal and regenerative capacity of HSCs in the adult BM vascular niche

Measurement of the branching fraction and CP content for the decay B 0rarrD* +D* $

We report a measurement of the branching fraction of the decay B 0rarrD* +D* - and of the CP-odd component of its final state using the BABAR detector. With data corresponding to an integrated luminosity of 20.4 fb -1 collected at the Upsi(4S) resonance during 1999-2000, we have reconstructed 38 candidate signal events in the mode B 0rarrD* +D* - with an estimated background of 6.2plusmn0.5 events. From these events, we determine the branching fraction to be B(B 0rarrD* +D* - )=[8.3plusmn1.6(stat)plusmn1.2(syst)] times10 -4. The measured CP-odd fraction of the final state is 0.22plusmn0.18(stat)plusmn0.03(syst

Simultaneous measurement of the B-0 meson lifetime and mixing frequency with B-0 -> D(*-)l(+)nu(l) decays RID C-2728-2008 RID C-5223-2009 RID C-5719-2008 RID D-1055-2009 RID A-2675-2009

We measure the B-0 lifetime tau(B)(0) and the B-0-(B) over bar (0) oscillation frequency Deltam(d) with a sample of approximately 14000 exclusively reconstructed B-0-->D(*-)l(+)nul signal events, selected from 23 million B (B) over bar pairs recorded at the Y(4S) resonance with the BABAR detector at the Stanford Linear Accelerator Center. The decay position of the other B is determined with the remaining tracks in the event, and its b-quark flavor at the time of decay is determined with a tagging algorithm that exploits the correlation between the flavor of the b quark and the charges of its decay products. The lifetime and oscillation frequencies are measured simultaneously with an unbinned maximum-likelihood fit that uses, for each event, the measured difference in decay times of the two B mesons (Deltat), the calculated uncertainty on Deltat, the signal and background probabilities, and b-quark tagging information for the other B. The results are tau(B)(0)=(1.523(-0.023)(+0.024)+/-0.022) ps and Deltam(d)=(0.492+/-0.018+/-0.013) ps(-1). The statistical correlation coefficient between tau(B)(0) and Deltam(d) is -0.22

Measurement of time-dependent CP asymmetries and the CP-odd fraction in the decay B-0 -> D*+D*- RID C-2728-2008 RID C-5223-2009 RID C-5719-2008 RID D-1055-2009 RID A-2675-2009

We present a measurement of time-dependent CP asymmetries and an updated determination of the CP-odd fraction in the decay B-0-->D*+D*- using a data sample of 88x10(6)B (B) over bar pairs collected by the BABAR detector at the PEP-II B Factory at SLAC. We determine the CP-odd fraction to be 0.063+/-0.055(stat)+/-0.009(syst). The time-dependent CP asymmetry parameters Im(lambda(+)) and \lambda(+)\ are determined to be 0.05+/-0.29(stat)+/-0.10(syst) and 0.75+/-0.19(stat)+/-0.02(syst), respectively. The standard model predicts these parameters to be -sin2beta and 1, respectively, in the absence of penguin diagram contributions