Biomedical Engineering Reference
In-Depth Information
SMCs. Nevertheless, it has been recently appreciated that VEGF also exerts
an effect on SMCs. In vitro studies indicate that VEGF may induce and
modulate vascular SMC proliferation and migration through the upregula-
tion of matrix metalloproteinases (69,74), and that VEGF receptors 1 and 2
are expressed in vascular SMCs (74,75). VEGF has been recently implicated
in SMC proliferation in systemic arteries. Experimental studies in animal
models show that VEGF may promote SMC proliferation and neointimal
formation after vascular injury (76), and that recombinant VEGF enhances
the progression of the atherosclerotic plaque (77,78). In humans, VEGF has
been related with the progression of coronary atherosclerosis (79). Accord-
ingly, it is conceivable that VEGF might contribute to the structural remo-
deling of pulmonary arteries in early stages of COPD, presumably by
enhancing the proliferation and intimal migration of SMCs.
Part of the biological actions of VEGF is related to NO-dependent
mechanisms (80). Inhibition of NO synthesis with L-NAME (N-nitro-l-
arginine methyl ester) upregulates the gene expression of VEGF and its
receptors (81). Further, long-term administration of L-NAME induces cor-
onary vascular arteriosclerosis (82) and significant increase of VEGF gene
expression (83). Furthermore, VEGF receptor blockade is associated with
reduced proliferative changes in coronary arteries (83). Overall, these find-
ings suggest that endothelial dysfunction and decreased NO synthesis, as
shown in patients with mil-to-moderate COPD (6,21), might promote
VEGF activity.
B. Transforming Growth Factor
The transforming growth factor-beta (TGF-
b
) family is a multifunctional
group of cytokines that play a central role in cell wound healing and tissue
repair. Among other properties, TGF-
b
proteins modulate cellular pro-
liferation and induce differentiation and synthesis of extracellular matrix
protein. At present, the TGF-
b
family consists of more than 25 isoforms
that, based on sequence analysis of bioactive domains, can be grouped into
at least eight subfamilies (84). Members of TGF-
b
family signal by simulta-
neously contacting two transmembrane serine
=
threonine kinases, known as
type I and type II receptors. Both receptors are required for TGF-
b
action.
In normal lungs, TGF-
b
protein and mRNA expression have been
identified in bronchial epithelial cells, alveolar macrophages, and SMCs
(85-88). The release and activation of TGF-
b
stimulates the production of
various extracellular matrix proteins and inhibits their degradation. In
COPD and asthma, TGF-
b
has been implicated in connective tissue
deposition (89,90) and airway macrophage recruitment (91).
TGF-
b
has been identified as a potential mediator of vascular remo-
deling in pulmonary hypertension (92).
In fact, mechanical
stretch
