Hypoxia-Inducible Factors and Adenosine Signaling in Vascular Growth - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 110

years, the role of adenosine as a potential stimulator of tissue oxygenation and ves-
sel growth has emerged [1]. In this chapter we will discuss the angiogenic potential
of adenosine receptors as driven by hypoxia in endothelial cells.
7.2 Endothelial Cells in Vascular Growth and Development
Endothelium constitutes a highly specialized organ that lines the vascular system
and lymphatic channels. Endothelial cells exhibit a great degree of heterogene-
ity that arises from their location as well as their specialization in response to
environmental cues (autocrine and paracrine factors, shear stress and pressure)
and pathophysiological stresses [5, 41]. Characterization of this heterogeneity and
study of associated functional changes is key to the development of therapeutic
approaches, such as those targeting angiogenesis. This point is well illustrated by
one such study that describes the gene expression profile of 53 cultured human
endothelial cell lines from arteries, veins and microvessels from 14 different tissues
[12]. In this study the patterns of gene expression that could distinguish between
endothelial cells of large and small vessels, and between those of veins and arteries,
were evaluated. Expression patterns of gene products from specialized endothelia
were related to functional roles such as transport of molecules, migration of immune
cells, neurogenesis, tracheal branching, and the establishment of the left/right asym-
metry of the body. Thus the transcriptional programs of endothelial cells from
different tissues and organs are specifically adapted during development to assume
distinct roles at each site. The pulmonary circulation represents a unique vascular
bed that receives 100% of the cardiac output. Although endothelial cells of pul-
monary artery and those of capillaries express classical endothelial cell markers,
they differ in critical roles such as barrier function and angiogenic potential [68].
Endothelial cell populations also contain significant numbers of proliferating pro-
genitor cells. Although each endothelial population may have a distinct number of
progenitor cells, they are phenotypically related to their vascular origin. Thus it is
also important to consider the contents and molecular programming of the endothe-
lial progenitor cells as they could play an essential role in vascular development,
homeostasis and repair after injury. With an improved understanding of signaling in
normal diverse endothelia one could develop strategies to target altered responses in
diseased or abnormal vessels.
Vascular growth and proliferation requires an early phase of vasculogenesis fol-
lowed by angiogenesis. Vasculogenesis involves the de novo formation of vessels
from progenitor cells. On the other hand, angiogenesis is a complex multistep pro-
cess involving endothelial cell invasion, migration and cell proliferation resulting in
formation of new blood vessels from pre-existing ones. Under physiological con-
ditions, angiogenesis is required for normal growth and development during fetal
life and also in tissue repair during adult life. Fetal lung develops in a hypoxic envi-
ronment (3-5% O 2 ). Such hypoxic environments activate signaling pathways that
increase vascular cell proliferation.