Drug Targeting Organ-Specific Strategies

7.3 Chronic Inflammatory Disorders 177
sequently, they proliferate and migrate towards the tumour or inflammatory site. Finally they
form a capillary lumen, after which vessel maturation takes place (for a more detailed description
of the molecular regulation of angiogenesis, see Chapter 9) [34].
The putative role of angiogenesis in chronic inflammatory diseases is the maintenance of
the inflammatory state by allowing ongoing recruitment of inflammatory cells and by supplying
nutrients and oxygen to proliferating inflamed tissue. The increased endothelial surface
creates an enormous capacity for the production of cytokines, adhesion molecules, and
other inflammatory stimuli [35].
In many chronic inflammatory diseases, angiogenesis can be identified in the inflamed lesions.
For example, in rheumatoid arthritis extensive neovascularization is present in the inflamed
synovium where it is one of the earliest histopathological findings [36]. Since in RA
synoviocytes exhibit characteristics of tumour cells, including somatic mutations in key regulatory
genes such as H-ras and the p53 tumour suppressor, RA can be viewed as a multicentric
tumour-like mass that invades and destroys its local environment [37]. Concurrent increased
endothelial cell turnover may contribute to microvascular dysfunction and thereby
facilitate persistent synovitis.
Although the identity of the factors that promote angiogenesis in RA specifically still remain
unclear, both synovial tissue and fluid are enriched in angiogenesis-promoting factors.
These include cytokines such as bFGF,VEGF, and IL-8, and soluble VCAM-1 and E-selectin
[38].
In other chronic inflammatory diseases elevated levels of angiogenic factors were also
found. In patients with psoriasis, skin lesions over-expressed IL-8 while the expression of one
of the inhibitors of angiogenesis, thrombospondin-1, was downregulated [39].
Neovascularization in artherosclerotic lesions may be regulated by VEGF, as this factor is
over-expressed by different cells in the plaque tissue [40–42]. The increased serum levels of
VEGF that correlate with disease activity in patients with Crohn’s disease and ulcerative colitis,
indicate a role for this cytokine in promoting inflammation. Most likely, increased vascular
permeability and/or wound healing via its pro-angiogenic activity are the basis for this effect
[43].
There is at present no consensus on whether inflammation and angiogenesis can exist independently
from each other. This is due to the lack of suitable marker-epitopes that cover
all stages of angiogenesis, resulting in an underestimation or misinterpretation of the occurrence
of angiogenesis.As cells of the immune system contribute significantly to the local production
of pro-inflammatory and pro-angiogenic factors, it is likely though, that inflammation
and angiogenesis affect each other to a considerable extent.
7.3.3 Activation Pathways of Endothelial Cells in Chronic Inflammation
Activation of endothelial cells leads to changes in endothelial cell properties such as loss of
vascular integrity, expression of adhesion molecules, antithrombotic to prothrombotic phenotype
changes, cytokine production and the upregulation of HLA molecules. All these diverse
effects can be attributed to the activation of transcription factors [44]. Of the presently
known transcription factors, NFκB is believed to be one of the most important in the regulation
of endothelial cell activation. After a stimulus at the cell surface which is caused by e.g.