SUMMARYCoordination between the vascular system and forming organs is essential for proper embryonic development. The vasculature expands by sprouting angiogenesis, during which tip cells form filopodia that incorporate into capillary loops. Although several molecules, such as vascular endothelial growth factor A (Vegfa), are known to induce sprouting, the mechanism that terminates this process to ensure neovessel stability is still unknown. Sphingosine-1-phosphate receptor 1 (S1P 1 ) has been shown to mediate interaction between endothelial and mural cells during vascular maturation. In vitro studies have identified S1P 1 as a pro-angiogenic factor. Here, we show that S1P 1 acts as an endothelial cell (EC)-autonomous negative regulator of sprouting angiogenesis during vascular development. Severe aberrations in vessel size and excessive sprouting found in limbs of S1P 1 -null mouse embryos before vessel maturation imply a previously unknown, mural cell-independent role for S1P 1 as an anti-angiogenic factor. A similar phenotype observed when S1P 1 expression was blocked specifically in ECs indicates that the effect of S1P 1 on sprouting is EC-autonomous. Comparable vascular abnormalities in S1p 1 knockdown zebrafish embryos suggest cross-species evolutionary conservation of this mechanism. Finally, genetic interaction between S1P 1 and Vegfa suggests that these factors interplay to regulate vascular development, as Vegfa promotes sprouting whereas S1P 1 inhibits it to prevent excessive sprouting and fusion of neovessels. More broadly, because S1P, the ligand of S1P 1 , is blood-borne, our findings suggest a new mode of regulation of angiogenesis, whereby blood flow closes a negative feedback loop that inhibits sprouting angiogenesis once the vascular bed is established and functional.

Recently, blood vessels have been implicated in the morphogenesis of various organs. The vasculature is also known to be essential for endochondral bone development, yet the underlying mechanism has remained elusive. We show that a unique composition of blood vessels facilitates the role of the endothelium in bone mineralization and morphogenesis. Immunostaining and electron microscopy showed that the endothelium in developing bones lacks basement membrane, which normally isolates the blood vessel from its surroundings. Further analysis revealed the presence of collagen type I on the endothelial wall of these vessels. Because collagen type I is the main component of the osteoid, we hypothesized that the bone vasculature guides the formation of the collagenous template and consequently of the mature bone. Indeed, some of the bone vessels were found to undergo mineralization. Moreover, the vascular pattern at each embryonic stage prefigured the mineral distribution pattern observed one day later. Finally, perturbation of vascular patterning by overexpressing Vegf in osteoblasts resulted in abnormal bone morphology, supporting a role for blood vessels in bone morphogenesis. These data reveal the unique composition of the endothelium in developing bones and indicate that vascular patterning plays a role in determining bone shape by forming a template for deposition of bone matrix.

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Zero-mean" optical potentials are used to manipulate dephasing of ultra-cold atoms confined in atom-optical billiards. Generic and non-generic perturbations result in qualitatively different dephasing properties. Different phase-space regimes are probed and identified.OCIS codes: (020.0020) Atomic and molecular physics Dephasing due to inhomogeneous trap perturbations is the main limiting factor to the coherence time of ultra-cold atoms confined in optical dipole traps. The dephasing due to inhomogeneous broadening can be reduced by the use of coherence echoes [1] and "compensating" techniques [2]. The suppression of inhomogeneous broadening allows for inherent dephasing related to irreversible interactions with the environment to be studied even for ensembles of atoms filling some 10 6 -10 8 levels of atom optics billiard, where the underlying classical motion is either regular, chaotic or mixed.Microwave echo spectroscopy is sensitive to minute perturbations caused by the trap itself, which drive dephasing by mixing quantum orbital trap states. Previously, we showed that when the perturbation and the trap share dynamical timescale and symmetry, a distinct revival of the echo coherence emerges even for classically-chaotic atom-optics billiards [3].Here, we use this sensitivity to consider a broader class of so-called "generic" perturbations, while minimizing the trap related dephasing using compensating techniques in which the interaction causing the dephasing is canceled by an additional interaction of opposite sign [2]. Optically trapped 85 Rb atoms at a temperature of ~25 µ K are initially prepared in their lower hyperfine state. The atoms are then subjected to a microwave echo π/2-π-π/2 pulse sequence. First a microwave π/2 pulse forms a superposition of both hyperfine states |5S 1/2 , F=2, m F =0> and |5S 1/2 , F=3, m F =0>, then the atoms evolve a time T, after which a refocusing π pulse exchange the populations of these two states, a second evolution of time T effectively reverses inhomogeneous effects and after a last π/2 the resulting dephasing directly measures to trap state mixing due to perturbations [1].We consider two extreme examples of generic perturbations in a compensated "wedge" billiard. In Fig. 1 we consider the case of complete spatial symmetry breaking of the perturbation and trap, by adding a weak spackle perturbation beam. The spackle beam is detuned to half the distance between the two hyperfine levels such that its associated dipole potential is time averaged over the whole echo sequence to zero, while its mixing effect is comparable to the uncompensated trap. The time scale associated with the spackle beam is smaller then all other dynamical timescales. Unlike the non-generic perturbation of the trap itself (blue circles in Fig. 1), the spackle field causes a monotonically increasing dephasing (red crosses in Fig. 1) reflecting the lack of a well defined timescale emerging from the perturbation. Furthermore, when the spackle generic perturbation strength is increased, the dephasing ra...