Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 605

10.2.2 Involved Factors in Angiogenesis

Numerous mechanisms are involved at various length scales: chemical signaling
and genetic response, cell interactions, and environmental stresses. 5 Computa-
tional simulations have been proposed to provide insights into structure-function
relationships at all involved scales [ 1173 ]. Vasculogenesis is modeled as traction-
driven remodeling of an initially uniform tissue in the absence of blood flow, and
angiogenesis as a flow-driven remodeling of a porous structure.
Development of vascular trees includes adaptation to mural stress field. An-
giogenic molecules are generated in response to hypoxia and other stimuli. An-
giopoietins , VEGF, and integrins regulate the vessel caliber. The expression of
angiopoietin TIE2 receptor characterizes 3 cell types that have angiogenic activity:
(1) endothelial cells; (2) TIE2 monocytes and their hematopoietic progenitors, and

(3) pericyte precursors of mesenchymal origin [ 1174 ].

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10.2.3 Endothelial Sprouting: Tip and Stalk Cells

Certain endothelial cells that will form the distal end of the sprout — tip cells —
strongly express vascular endothelial growth factor VEGFR2 receptor. Once en-
dothelial cells are selected for sprouting, sprouting is controlled by the balance
between angiogenic signals (e.g., VEGF and ephrin-B2; Tables 10.1 and 10.2 )and
antagonists (tight contacts with pericytes recruited by platelet-derived growth factor-
B, certain extracellular matrix components, and VEGF inhibitors).
Endothelial sprouting for angiogenesis requires the coordinated behavior of
involved endothelial cells that is regulated by the Notch and VEGFR signalings.
Selection of endothelial cells for tip cell position depends on the ratio between
VEGFR1 and VEGFR2 receptors [ 1175 ]. Receptor VEGFR1 has a high affinity
for VEGFa, but a weak kinase activity. It modulates VEGFa signaling via VEGFR2
receptor. Whereas signaling launched by VEGFR2 and VEGFR3 supports tip cells,
the decoy receptor VEGFR1 limits tip cell formation [ 886 ]. In addition, alternative
splicing of VEGFR1 transcript generates a secreted, inactive isoform (soluble
VEGFR1 S ), which serves as a sink for free VEGFa factor.
Alternative splicing of the VEGFA transcript creates many variants with dis-
tinct functions. Migration of endothelial cells and, hence, vascular branching
are promoted by heparan sulphate-binding VEGFa 165 variant. Free VEGFa 121
variant influences endothelial cell proliferation, but not migration [ 886 ]. Moreover,
VEGFR2 output elicited by matrix-bound VEGFa differs from that primed by
soluble VEGFa messenger.

5 Vascular network development is regulated by local interactions between vascular cells and
hemodynamic conditions.