Biomedical Engineering Reference
In-Depth Information
from the media through the internal elastic lamina, dedifferentiate, and pro-
liferate into the intima. Yet, very few studies have documented SMCs
migrating across the internal elastic lamina, from the media into the intima
(32). A second possibility is that intimal SMCs may arise from a preexisting
precursor cell that after specific stimulus proliferates and differentiates into
SMCs. Studies conducted in an hypoxic rat model have shown that SMCs
developing in small arteries originate from pericytes, a cell type found in
the walls of nonmuscularized arterioles, and from intermediate cells in par-
tially muscularized arteries (33,34). A third possibility is that SMCs might
originate from an external source. Recent studies have shown that bone
marrow cells have the potential to give rise to vascular progenitor cells that
have the capacity to mobilize, home to sites of vascular injury and differenti-
ate into endothelial or SMCs, contributing to vascular repair, remodeling,
and lesion formation (35). Experimental studies, combining bone marrow
transplantation and models of vascular injury, have demonstrated that reci-
pients' bone marrow cells may contribute to SMC proliferation and neoin-
timal formation. This mechanism has been shown in graft-associated
vasculopaty, arterial remodeling after mechanical injury, and atherosclerotic
plaque formation (36). In a recent study conducted in a bovine model of
hypoxia-induced pulmonary hypertension, Davie et al. (37) showed that
cells expressing the transmembrane tyrosine kinase receptor for stem cell
factor, c-kit, are mobilized from the bone marrow in response to hypoxia,
and that cells expressing c-kit are present in the remodeled vessel walls.
To what extent this mechanism might contribute to pulmonary vascular
remodeling in COPD has not been determined yet.
D. Potassium Channels and Smooth Muscle Cell Function
Membrane potassium (K
þ
) channels in vascular SMCs play an essential role
in the regulation of membrane potential and, therefore, vascular tone (38).
Closure of K
þ
channels reduces K
þ
efflux and causes membrane depolariza-
tion, which opens voltage-gated Ca
2
þ
channels, leading to an increase in
intracellular Ca
2
þ
concentration and vasoconstriction. Using patch-clamp
electrophysiology, three families of K
þ
channels have been identified in vas-
cular SMCs: delayed-rectifier K
þ
channels (K
DR
); large conductance, calcium
activated K
þ
channels (K
Ca
); and ATP-sensitive K
þ
channels (K
ATP
). Potas-
sium channels are important in pulmonary circulation because they have been
closely related with hypoxic vasoconstriction, since hypoxia can cause both an
inhibition of whole cell K
þ
current and membrane depolarization in isolated
pulmonary artery smooth muscle cells (PASMCs) (39). In addition to these
pathways, NO has been shown to act directly on some K
þ
channels (40).
The mechanisms by which changes in oxygen are sensed and K
þ
chan-
nel activity is modified have not been identified. Some studies have suggested
that changes in the redox status of PASMCs cytoplasm to a more reduced
