Biomedical Engineering Reference
In-Depth Information
pathobiology of pulmonary hypertensive disorders is currently under
extensive investigation.
A. Vascular Endothelial Growth Factor
Vascular endothelial growth factor (VEGF) is a glycoprotein with impor-
tant actions on cell function, which is abundantly expressed in the lung.
Immunohistochemistry of lung tissue sections has revealed VEGF protein
in endothelial cells, vascular SMCs, macrophages, and airway epithelial cells
(13). This molecule exerts a critical role in vascular homeostasis, since it
stimulates endothelial cell growth and proliferation, and promotes angio-
genesis under physiologic and pathologic conditions. In addition, VEGF
is critical for endothelial cell survival by inhibiting apoptosis (68), stimulates
vascular SMC proliferation (69), exerts a vasodilator effect, and increases
vascular permeability (70). Indeed, VEGF was previously known as vascular
permeability factor (VPF).
VEGF has been involved in pulmonary vascular remodeling in pri-
mary pulmonary hypertension, which is characterized by endothelial and
SMC proliferation (71). Santos et al. (13) evaluated the expression of VEGF
in COPD. Patients with mild-to-moderate COPD showed increased expres-
sion of VEGF in pulmonary muscular arteries, as compared with control
nonsmokers. The immunohistochemical analysis showed strong VEGF
expression in endothelial cells and also in SMCs proliferating in hyperplasic
intimas. The number of arteries showing positive immunoreaction to VEGF
in the arterial wall was greater, and the intensity of the immunoreaction
stronger, in patients with mild-to-moderate COPD than in control nonsmo-
kers (13). In that study, it was also shown an enhanced expression of VEGF
in pulmonary muscular arteries of smokers with normal lung function, sug-
gesting that upregulation of VEGF could be more likely related to pulmon-
ary vascular changes associated with cigarette smoking rather than to
COPD per se. Indeed, in patients with advanced COPD and severe emphy-
sema, the expression of VEGF in pulmonary arteries was lower than in
patients with mild-to-moderate disease and did not differ from control non-
smokers (13). This could be associated with a generalized downregulation of
VEGF in patients with emphysema that might lead to endothelial cell apop-
tosis, thereby contributing to the pathogenesis of emphysematous lung
destruction, as suggested by Kasahara et al. (72). In the study by Santos
et al. (13), the expression of VEGF in SMCs correlated with the thickness
of the arterial wall, suggesting a potential role of VEGF in the pathogenesis
of pulmonary vascular remodeling. Indeed, VEGF has been suggested to
exert a pathogenic role in primary pulmonary hypertension due to its known
effects inducing endothelial cell proliferation (73). In COPD, the role of
VEGF is less apparent since endothelial cells conform a monolayer, as in
normal conditions, whereas cells proliferating in pulmonary arteries are
