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

Abstract：

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.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Chappell JC,Cluceru JG,Nesmith JE,Mouillesseaux KP,Bradley VB,Hartland CM,Hashambhoy-Ramsay YL,Walpole J,Peirce SM,Mac Gabhann F,Bautch VL

doi

10.1093/cvr/cvw091

subject

Has Abstract

pub_date

2016-07-01 00:00:00

pages

84-93

issue

eissn

0008-6363

issn

1755-3245

pii

cvw091

journal_volume

111

pub_type

杂志文章

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