Role of Purine-Converting Ecto-Enzymes in Angiogenic Phenotype of Pulmonary Artery Adventitial Vasa Vasorum Endothelial Cells of Chronically Hypoxic Calves - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 71

5.1 Introduction
Extracellular adenine nucleotides have long been known as regulators of vas-
cular tone, permeability, and homeostasis. However, the ability of extracellular
nucleotides to control cell growth and proliferation remains poorly investigated. The
variety of studies that have been performed on endothelial cells isolated from large
systemic and pulmonary vessels that would presume the endothelial cells from these
sources/tissues exhibit quiescent or differentiated phenotype with a limited angio-
genic capacity. Keeping this in mind, we have developed an animal model system
that allows investigation of phenotypical and functional properties of microvascu-
lar endothelial cells derived from the sites of active angiogenesis. These cells are
vasa vasorum endothelial cells (VVEC) isolated from microvascular network that
grow extensively within the pulmonary artery adventitial compartment of chroni-
cally hypoxic calves. This chapter summarizes our recent findings on the role of
extracellular nucleotides as potent angiogenic activators of VVEC as well as on the
role of purine-converting enzymes potentially contributing to angiogenic properties
of VVEC under chronic hypoxic condition.
5.2 Hypoxia-Induced Vascular Remodeling and Vasa Vasorum
Angiogenesis
Pathologic vascular remodeling plays a pivotal role in the progression of a variety
of diseases and conditions where hypoxia, ischemia, or inflammation are prominent
features [7, 13]. Using a neonatal model of pulmonary hypertension, we previously
demonstrated that significant changes in the structure of pulmonary vessels accom-
pany the hypertensive process and include marked thickening of both the media and
adventitia with particularly striking fibroproliferative changes observed in adventi-
tia of chronically hypoxic calves [17, 78]. Angiogenesis, a process of blood vessel
expansion, can be observed in response to various stress conditions of microvascu-
lar beds such inflammation and fibrosis. In this context, it is important to note that
the adventitial compartment of at least elastic and large muscular arteries, includes
within its borders, a microcirculatory network, the vasa vasorum. The vasa vaso-
rum network has traditionally been assigned a passive role in maintaining vessel
integrity through the supply of oxygen and nutrients to the outer part of the vessel
wall. However, recent studies have demonstrated that extensive neovascularization
of the vasa vasorum may contribute to the progression of vascular diseases in the
systemic circulation including atherosclerosis, restenosis, vasculitis type II diabetes
and metabolic syndrome [34, 35, 43, 60, 71] Our group has demonstrated that
marked neovascularization of the vasa vasorum of the pulmonary circulation has
been observed in neonatal calves exposed to chronic hypoxia (Fig. 5.1). It has also
been shown that angiogenesis of the pulmonary circulation can be observed in a
form of plexiform lesions in the lung of patients with primary pulmonary hyperten-
sion, CREST and HIV infections [15, 56, 82]. In severe pulmonary hypertension