Recent Advances in Angiogenesis and ... - Bentham Science

30 Recent Advances in Angiogenesis and Antiangiogenesis, 2009, 30-39
Cross-Link Between Inflammation and Angiogenesis
Enrico Crivellato and Domenico Ribatti
Domenico Ribatti (Ed.)
All rights reserved - © 2009 Bentham Science Publishers Ltd.
CHAPTER 4
Department of Medical and Morphological Researches, Anatomy Section, University of Udine Medical School,
Udine, Italy and Department of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy
Correspondence to: Prof. Enrico Crivellato, Department of Medical and Morphological Researches, Anatomy
Section, Piazzale Kolbe, 3, 33100 Udine, Italy. Tel: 0039.0432.494221; Fax: 0039.0432.494201; Email:
enrico.crivellato@uniud.it
1. INTRODUCTION
Abstract: Angiogenesis refers to the formation of new blood vessels from pre-existing vascular
structures, i.e. capillaries and post-capillary venules. This process occurs in different
conditions, such as embryo development and post-natal tissue growth, inflammation like wound
healing and chronic allergies, and cancer. Both structural cells and inflammatory cells in the
different tissues are involved in the mechanisms of endothelial cell proliferation, migration and
activation, through the production and release of a large spectrum of pro-angiogenic mediators.
These may create the specific micro-environment that favours an increased rate of tissue
vascularization. In this review, we will present the most recent findings on the contribution of
inflammatory cells to the development and progression of inflammation-associated
angiogenesis. We will also provide some insight of the complex signaling network, which links
each inflammatory cell to the surrounding scenario.
Angiogenesis is a complex and highly orchestrated
process leading to the formation of new blood vessels
from pre-existing capillaries and venules [1]. This
process is fundamental for organ development. During
the later stages of embryogenesis, the vascularization
of many tissues occurs by angiogenesis. This
mechanism of vessel production consists in a
multistep and highly orchestrated process, which is
under control of different genetic and epigenetic
mechanisms [2]. There are at least two types of
angiogenesis: (a) the so-called “sprouting”
angiogenesis, which is characterized by the
proliferation and migration of endothelial cells into
avascular sites; (b) the “non-sprouting” angiogenesis
or intussusceptive microvascular growth, which occurs
by splitting of the existing vasculature by transluminal
pillars or transendothelial bridges [1, 3]. In the adult
life, angiogenesis accompanies various physiological
and pathophysiological conditions, such as ovulation,
endometrial vascularization in menstrual cycle and
pregnancy, and wound healing.
There is increasing evidence to support the view that
angiogenesis is an integral component of a diverse
range of chronic inflammatory and autoimmune
diseases, including atherosclerosis, rheumatoid
arthritis, diabetic retinopathy, psoriasis, airway
inflammation, peptic ulcers, and Alzheimer’s disease
[4]. Indeed, angiogenesis is intrinsic to chronic
inflammation and is associated with structural
changes, including activation and proliferation of
endothelial cells, capillary and venule remodeling, all
of which result in expansion of the tissue
microvascular bed. Chronic inflammation in the
airways, for instance, is associated with dramatic
architectural changes in the walls of the airways and in
the vasculature they contain. Therefore, it seems that
an imbalance in favour of pro-angiogenic factors leads
to the abnormal growth of new blood vessels in
asthma. Inflammatory diseases, such as rheumatoid
arthritis and psoriasis, are characterized by proliferating
tissue containing an abundance of inflammatory cells
and newly formed blood vessels. During prolonged
inflammatory reactions, many structural and resident
cells, such as fibroblasts, epithelial cells, smooth
muscle cells, mast cells, and/or infiltrating cells, such
as monocytes/macrophages, neutrophils, lymphocytes
and eosinophils, synthesize and secrete pro-angiogenic
factors that promote neovascularization. The anatomic
expansion of the microvascular bed combined with its
increased functional activation can therefore foster
further recruitment of inflammatory cells, and
angiogenesis and inflammation become chronically
codependent processes. In addition, many of the
mediators that are fundamental players in angiogenesis
are also inflammatory molecules. Inflammationassociated
angiogenesis also occurs during
pathophysiological reactions, like wound healing and
scar formation. The process of extracellular matrix
remodeling that accompanies this kind of tissue
responses is strictly dependent upon angiogenic
events. Inflammatory cells contribute even to