Biology Reference
In-Depth Information
component of CR is an accelerated form of arteriosclerosis known as transplant
vascular sclerosis (TVS). TVS is characterized histologically by diffuse concen-
tric intimal proliferation that ultimately occludes the vessel (Billingham 1992). A
growing body of evidence supports a role for angiogenesis and tissue repair proc-
esses in the development of vascular disease (Shibata et al. 2001; Khurana and
Simons 2003). A sparse number of macrophages, T cells, NK cells, and B cells
are seen in early lesions, while late lesions are associated with a thickened intima
containing SMC interspersed with macrophages (Clinton and Libby 1992).
Activated inflammatory cells and SMC within and near vascular lesions are
important local sources of pro-angiogenic factors (Bouis et al. 2006). TVS devel-
opment involves chronic perivascular inflammation, endothelial cell (EC) dys-
function, and SMC migration from the media to the intima and proliferation that
result in deposition of extracellular matrix (ECM) and neointimal thickening of
the allograft arterial wall (Libby et al. 1989; Billingham 1992; Hosenpud et al.
1992). These events result in vessel narrowing, occlusion, and graft failure. The
pathological processes involved in TVS and other vascular diseases are akin to
many of the cellular events that mediate normal tissue repair/angiogenesis. In all
cases, a complex interaction between cells and surrounding regulatory factors,
enzymes, and ECM components leads to cellular migration, proliferation, and
tissue remodeling.
The formation of new blood vessels or angiogenesis is broadly divided into
the following three phases: vessel destabilization, proliferation/migration, and
vessel maturation (Carmeliet 2003). In normal adults, angiogenesis is normally
restricted to formation of placental and endometrial tissue, hair follicle vascu-
larization, and tissue repair. During these processes, the endothelium remains
inactive due to a balance of positive and negative regulatory factors. When
vessel growth is required, the regulatory balance tips toward pro-angiogenic
factors. Restoration of steady state is achieved by increasing angiogenesis
inhibitors and vessel stabilization factors. Breakdown of the tightly regulated
angiogenic balance leads to abnormal angiogenesis and contributes to a variety
of pathological disorders, including cancer, autoimmune conditions, and
cardiovascular disease (Carmeliet 2003). Leukocytes play a role in normal
angiogenesis through contribution of pro- and anti-angiogenic factors, but are
particularly important in pathological (immune- or tumor-driven) angiogenesis
(Kent and Sheridan 2003).
Wound healing (WH) is a complex process involving the sequence of inflamma-
tion, tissue formation, and tissue remodeling, which results in the re-establishment
of an anatomical or physiological barrier (Kent and Sheridan 2003). Wound healing
involves a local milieu created by the coordinated action of growth factors,
cytokines, enzymes, and extracellular matrix (ECM) components, interacting with
the injured tissue. In addition, an influx of inflammatory cells is involved in this
process. Angiogenesis itself is an important component of WH. Given the role of
inflammation, new vessel growth and tissue remodeling in WH, it is not surprising
that many of the same stimulatory and inhibitory factors promote both angiogenesis
and WH (Werner and Grose 2003).
