Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 632

cells, upon delivery by microvesicles, miR9 decreases the abundance of SOCS5,
an antagonist of the JAK-STAT pathway [ 1238 ]. Activated Janus kinase-1 and -2
phosphorylate signal transducer and activator of transcription STAT1 and STAT3.

10.6.4 Morphogens

Morphogens govern positions of various cell types in a developing tissue. These
signaling substances build concentration gradients to generate and maintain the
transcription of target genes at given concentration thresholds. Hence, genes may
determine the anatomical structure of an organism [ 1239 ]. 38

10.6.4.1 Notch

Notch components mediate the arterial gene program, 39 the venous specification
via the nuclear receptor NR2f2, 40 and the lymphatic commitment via Prospero
homeobox gene product Prox1 [ 1167 ]. 41 Most lymphatics differentiate from veins.
The formation of endothelial tip cells at the leading edge of vascular sprouts is
regulated by DLL4-Notch-1 signaling that is specific to the vasculature. Vascular-
specific Delta-like ligand-4 regulates proliferation and differentiation of endothelial
cells and vascular development. The Notch ligand DLL4 is expressed during
vascular remodeling. Notch signaling initiated by DLL4 and restricted to the
vascular system is involved in arteriovenous differentiation.

38 Mathematical reaction-diffusion discretized and continuous models of pattern formation rep-
resent either cells as points or as local physicochemical characteristics in a continuum. In the
cell form of the model, mechanical aspects are related to cell positions, masses, velocities, and
elastic properties, as well as intercellular forces, and chemical aspects to the chemical composition
and diffusivity of each separate cell. In the continuous form of the model, mechanical aspects
are described by stress, velocity, density, and elasticity of the matter, and chemical aspects by
concentration and diffusivity in each point. Chemical reactions include production, conversion,
and degradation of morphogens.
39 Delta-like ligand DLL4 is a Notch agonist via Notch-1 and Notch-4 receptors devoted to the
specific development of the arterial endothelium.
40 Nuclear receptor NR2f2, or chicken ovalbumin upstream promoter transcription factor
COUPTF2, inhibits the activity of many transcription factors, such as intracellular receptors
retinoic acid (RAR or NR1b), retinoid X (RXR or NR2b), and thyroid (TR or NR1a) and steroid
hormone (SF1 or NR5a1) receptors. Transcription factor NR2f2 is able to bind to DNA either as
a homo- or heterodimer. Two NR2f types are encoded by the NR2F1 and NR2F2 genes. Factor
NR2f2 is highly expressed in the venous endothelium, but not the arterial one. Transcription factor
NR2f2 is also involved in the formation of atrioventricular septum and coronary vessels.
41 The homeobox gene product Prox1 is expressed in certain endothelial cells that yield buds from
veins to give rise to lymphatics.