Flt-1 (VEGFR-1) coordinates discrete stages of blood vessel formation.

Autor:	Chappell JC; Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA Center for Heart and Regenerative Medicine Research, Virginia Tech Carilion Research Institute, Roanoke, VA 24014, USA., Cluceru JG; Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Nesmith JE; Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Mouillesseaux KP; Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Bradley VB; Center for Heart and Regenerative Medicine Research, Virginia Tech Carilion Research Institute, Roanoke, VA 24014, USA., Hartland CM; Center for Heart and Regenerative Medicine Research, Virginia Tech Carilion Research Institute, Roanoke, VA 24014, USA., Hashambhoy-Ramsay YL; Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21218, USA., Walpole J; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA., Peirce SM; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA., Mac Gabhann F; Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21218, USA., Bautch VL; Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA bautch@med.unc.edu.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2016 Jul 01; Vol. 111 (1), pp. 84-93. Date of Electronic Publication: 2016 May 03.
DOI:	10.1093/cvr/cvw091
Abstrakt:	Aims: In developing blood vessel networks, the overall level of vessel branching often correlates with angiogenic sprout initiations, but in some pathological situations, increased sprout initiations paradoxically lead to reduced vessel branching and impaired vascular function. We examine the hypothesis that defects in the discrete stages of angiogenesis can uniquely contribute to vessel branching outcomes. Methods and Results: Time-lapse movies of mammalian blood vessel development were used to define and quantify the dynamics of angiogenic sprouting. We characterized the formation of new functional conduits by classifying discrete sequential stages-sprout initiation, extension, connection, and stability-that are differentially affected by manipulation of vascular endothelial growth factor-A (VEGF-A) signalling via genetic loss of the receptor flt-1 (vegfr1). In mouse embryonic stem cell-derived vessels genetically lacking flt-1, overall branching is significantly decreased while sprout initiations are significantly increased. Flt-1(-/-) mutant sprouts are less likely to retract, and they form increased numbers of connections with other vessels. However, loss of flt-1 also leads to vessel collapse, which reduces the number of new stable conduits. Computational simulations predict that loss of flt-1 results in ectopic Flk-1 signalling in connecting sprouts post-fusion, causing protrusion of cell processes into avascular gaps and collapse of branches. Thus, defects in stabilization of new vessel connections offset increased sprout initiations and connectivity in flt-1(-/-) vascular networks, with an overall outcome of reduced numbers of new conduits. Conclusions: These results show that VEGF-A signalling has stage-specific effects on vascular morphogenesis, and that understanding these effects on dynamic stages of angiogenesis and how they integrate to expand a vessel network may suggest new therapeutic strategies. (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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