Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 607

Table 10.2. Endothelial sprouting ( Part 2 ); Source: [ 886 ]; ALK: activin receptor-like kinase;
Ang: angiopoietin; aPKC: atypical protein kinase-C; EPH: erythropoietin-producing hepatocyte
receptor kinase Par: partitioning defective protein; PAK: P21-activated kinase; PDGF: platelet-
derived growth factor; PDGFR: PDGF receptor; RasIP: RAS-interacting protein; S1P: sphingosine
1-phosphate; T receptor; TGF: transforming growth factor; TIE: Tyr kinase with Ig

and EGF homology domains (angiopoietin receptor); VEGF: vascular endothelial growth factor;
VEGFR: VEGF receptor; vSMC: vascular smooth muscle cell). Prior to tubulogenesis, or lumeno-
genesis, the apicobasal polarity is established in endothelial cells arranged in a string (precursor
vessel). Protein PAR3 is a major determinant of cell polarity that influences lumenogenesis. Cell
adhesion proteins (e.g., zonula occludens ZO1, claudin-5, and cadherin-5) move from the apical
(wetted) surface to the basolateral segment of the plasma membrane; at the basal surface, integrins
connect to matrix constituents. Integrin, PAR3, and RasIP1 promote the lateral redistribution
of these junctional components. Lumenogenesis is initiated, at least partly, by relocalization of
sialomucin CD34 and podocalyxin (Podxl) to the apical surface mediated by cadherin-5 and

β R: TGF β

1 -
integrins. Kinase PKC phosphorylates moesin that links to apical Podxl-CD34 complexes and
promotes the deposition of filamentous actin. Podocalyxin may cause an electrostatic repulsion of
apical surfaces between endothelial cells. Lumenal expansion may result from vacuole exocytosis
and fusion at the apical surface as well as signaling pathways, such as VEGFa-VEGFR2 axis
that recruits of myosin-2 to the apical surface and those that activate RoCK to foster actomyosin
filament contraction. Certain macrophage populations may act as cellular chaperones for vascular
anastomosis.

β

Event Factors

Tubulogenesis Par3/6, integrins,

(lumenogenesis) RasIP1, RhoGAP29, CDC42, Rac1,

Src, aPKC, PAK2/4, Raf

Anastomosis Macrophage

Stabilization PDGFb, TGF β 1

and (PDGFR β+ pericyte and SMC recruitment),

maturation S1P-S1P 1 , Ang1-TIE2, ephrin-B2-EPH

(mural-endothelial cell attachment),
TGF β 1-T β R2-ALK5
(vSMC differentiation),
deposition of the basement membrane,
strengthening of intercellular junctions)

according to the feature of VEGFR-DLL4-Notch signaling, which is constantly
re-evaluated.
Endothelial sprouts are converted into functional vessels. Sprout extension
involves the local proliferation and migration of the endothelial cells behind the
tip that forms the sprout stalk. Tip cells do not proliferate.
Navigation cues are sensed by tip cells. The navigators Uncoordinated-5 ho-
molog Unc5b, Roundabout homolog Robo4, plexin-D1, neuropilins, ephrin-B2, and
EPHb4 receptor are major conductors of angiogenesis. The growing endothelial
sprout is guided by attractive (e.g., netrins) and repulsive cues (e.g., semaphorin-
3). MicroRNAs ensure the post-transcriptional control of angiogenesis.