http://circres.ahajournals.org/content/early/2012/09/10/CIRCRESAHA.112.279109.abstract
Abstract
Rationale:
The density of native (pre-existing) collaterals varies widely and is a
significant determinant of variation in severity
of stroke, myocardial infarction and peripheral
artery disease. However, little is known about mechanisms responsible
for
formation of the collateral circulation in
healthy tissues.
Objective:
We previously found that variation in VEGF expression causes
differences in collateral density of newborn and adult mice.
Herein, we sought to determine mechanisms of
collaterogenesis in the embryo and the role of VEGF in this process.
Methods and Results: Pial collaterals begin forming between embryonic day (E) 13.5 and 14.5 as sprout-like extensions from arterioles of existing
cerebral artery trees. Global VEGF-A overexpressing mice (Vegf hi/+) formed more-and Vegf lo/+ formed fewer-collaterals during embryogenesis, in association with differences in vascular patterning. Conditional global
reduction of Vegf or Flk1 only during collaterogenesis significantly reduced collateral formation, but now without affecting vascular patterning, and
the effects remained in adulthood. Endothelial-specific Vegf reduction had no effect on collaterogenesis. Endothelial-specific reduction of a disintegrin-and-metalloprotease-domain-10
(Adam10) and inhibition of γ-secretase increased collateral formation, consistent with their roles in VEGF-induced Notch1 activation
and suppression of "pro-sprouting" signals. Endothelial-specific knockdown of Adam17 reduced collateral formation, consistent with its roles in endothelial cell migration and embryonic vascular stabilization,
but not in activation of ligand-bound Notch1. These effects also remained in adulthood.
Conclusions:
Formation of pial collaterals occurs during a narrow developmental
window via a sprouting angiogenesis-like mechanism, requires
paracrine VEGF-stimulation of Flk1-Notch
signaling, and adult collateral number is dependent on embryonic
collaterogenesis.
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