Local Guidance of Emerging Vessel Sprouts Requires Soluble Flt-1

Abstract

Summary Blood vessel networks form via sprouting of endothelial cells from parent vessels. Extrinsic cues guide sprouts once they leave the initiation site, but these cues are likely insufficient to regulate initial outward movement, and many embryonic vessel networks form in the absence of a strong extrinsic gradient. We hypothesized that nascent sprouts are guided by spatial cues produced along their own vessels, and that soluble Flt-1 (sFlt-1) participates in this guidance. Analysis of developing vessels with perturbed flt-1 function revealed mis-guided emerging sprouts, and transgenic sFlt-1 rescued sprout guidance parameters. sFlt-1 activity in endothelial cells immediately adjacent to the emerging sprout significantly improved local sprout guidance. Thus we propose that a vessel-intrinsic system initially guides emerging sprouts away from the parent vessel, utilizing spatially regulated expression of sFlt-1 in conjunction with exogenous VEGF. Local sprout guidance defects are predicted to contribute to vessel dysmorphogenesis during perturbed development and disease.

Human aging and CD31+T-cell number, migration, apoptotic susceptibility, and telomere length

“…Two critically important chemokines involved in vascular repair and homeostasis are VEGF and SDF-1␣. VEGF has been deemed the "master-regulator" of angiogenesis due to its role in endothelial proliferation and initiation of vessel sprouting (7,8). SDF-1␣ is an important agent in CXCR4-dependent hematopoietic cell migration and cell growth (42).…”

Blood vessel anastomosis is spatially regulated by Flt1 during angiogenesis

“…Global or vascular-selective deletion of Flt1 in mouse postnatal retinal vessels increases overall sprouting (Chappell et al, 2009;Ho et al, 2012;J.C.C. and V.L.B., unpublished).…”

VEGF-Directed Blood Vessel Patterning: From Cells to Organism

“…1B) (Kendall and Thomas 1993), and the differential effects of these isoforms on vessel patterning suggest that VEGF signaling is spatially regulated by localized Flt-1 expression (Kappas et al 2008;Chappell et al 2009). …”

“…We recently proposed a model whereby initial stochastic differences in sFlt-1 production by individual endothelial cells of a developing vessel result in increased expression of sFlt-1 by cells adjacent to an emerging sprout, and this expression is proposed to provide localized VEGF inactivation and thus more active ligand in the area immediately ahead of the migrating sprout (Fig. 2) (Chappell et al 2009). Evidence for this model of Flt-1-dependent local sprout guidance is that vessels lacking flt-1 have misguided sprouts, and mosaic analysis reveals a requirement for sFlt-1 in endothelial cells immediately adjacent to the sprout for proper sprout guidance.…”