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proliferation, migration, capillary tube formation and Galiano et al. found that topical VEGF accelerates wound
[78]
deposition of ECM. [60,61] healing in a diabetic mouse model.
The angiopoietins are members of the VEGF family, which Weinheimer‑Haus et al. found that low intensity
[79]
is largely specific for vascular endothelium. They include a vibration (LIV) applied vertically at 45 Hz with peak
naturally occurring agonist, Ang‑1, and antagonist, Ang‑2, acceleration of 0.4 g for 30 min a day for 5 days a week
both of which act by means of the Tie‑2 receptor. Two starting on the day of injury in diabetic mice increases
new angiopoietins, Ang‑3 in mice and Ang‑4 in humans, expression of pro‑healing growth factors and chemokines
have been identified, but their function in angiogenesis is (insulin‑like growth factor‑1, VEGF and monocyte
unknown. [62] chemotactic protein‑1) in wound environment. Though
there was no evidence of a change in the phenotype
Mast cell tryptase, stored in granules of activated mast cells,
is an additional angiogenesis factor that directly degrades of CD11b+ macrophages, however, LIV resulted in
the ECM components or release matrix‑bound growth trend toward a less inflammatory phenotype in the
factors by its proteolytic activity, [63,64] and acts indirectly CD11b2 cells which comprised of fibroblasts, endothelial
by activating latent matrix metalloproteases. The addition cells and/or keratinocytes. These findings indicate that
of tryptase to microvascular endothelial cells cultured on LIV may exert beneficial effects on wound healing by
a basement membrane matrix (matrigel) caused a marked enhancing angiogenesis and granulation tissue formation,
increase in capillary growth. Furthermore, tryptase can and these changes are associated with an increase in
[79]
induce endothelial cell proliferation in a dose‑dependent pro‑angiogenic growth factors.
manner, whereas specific tryptase inhibitors suppress the Venous insufficiency ulcers
capillary growth. [65] Venous insufficiency ulcers or venous stasis ulcers result
from incompetent valves in lower extremity veins, leading
IMPAIRED ANGIOGENESIS IN CHRONIC to venous stasis and hypertension that makes the skin
WOUNDS susceptible to ulceration. Pathological findings associated
with venous stasis ulcers include microangiopathy,
Angiogenesis is impaired in all chronic wounds leading fibrin “cuffing” and trapping of leukocytes within the
to further tissue damage results from chronic hypoxia microvasculature. [80,81]
and impaired micronutrient delivery. Specific defects have Chronic venous stasis ulcer patients have elevated levels
been identified in diabetic ulcers, venous insufficiency of VEGF in their circulation. This may explain the
[82]
ulcers and ischemic ulcers. vascular permeability and increased transudation of serum
Diabetic ulcers fluid in their wounds. Biopsies of these ulcers reveal
Patients with diabetes show abnormal angiogenesis in microvessels that are surrounded by fibrin cuffs composed
various organs. Vasculopathies associated with diabetes of fibrin and plasma proteins, such as α‑macroglobulin,
include abnormal blood vessel formation (e.g. retinopathy, thought to compromise gas exchange. [83‑85] Clinical studies
nephropathy) and accelerated atherosclerosis leading have shown that transcutaneous oxygen tension may be
to coronary artery disease, peripheral vascular disease, up to 85% lower in venous stasis ulcers compared with
[86]
and cerebrovascular disease. However, in diabetics, normal skin regions. VEGF expression is up‑regulated by
[65]
angiogenesis is decreased resulting in poor formation hypoxia, which further exacerbates vascular permeability,
[66]
of new blood vessels and thus decreased entry of formation of pericapillary fibrin cuffs and compromised
inflammatory cells and their growth factors. Growth factors gas exchange, which ultimately reduces growth factor
such as FGF‑2 and PDGF, essential for wound healing availability in the wound. [87,88] VEGF promotes the
have been found to be reduced in experimental diabetic formation tortuous, aberrant glomeruloid‑like vascular
[89]
wounds models. [67‑70] Furthermore, in rat models, topical structures found in granulation tissue. Laboratory
administration of high glucose to wounds was shown to animals treated with VEGF form these glomeruloid
[71]
inhibit the normal angiogenic process, suggesting a direct vascular structures within 3 days and are characterized
[90]
role for high glucose levels in diminished angiogenesis. by poor perfusion. In venous ulcers, the persistence of
glomeruloid vessels may interfere with oxygen delivery
Vascular endothelial growth factor plays an important and delay healing. In chronic venous stasis ulcers,
role in vascular growth and has been shown to be high levels of proteases such as neutrophil elastase,
deficient in diabetic wounds in experimental and clinical MMPs and urokinase‑type plasminogen activator are
models. Studies have shown that modulation of present. Concomitantly, there are decreased levels
[72]
[91]
oxidative damage or inhibition of the receptors for of protease inhibitors, such as plasminogen activator
[73]
advanced glycation end products improve wound healing inhibitor‑2. Excessive protease activity may degrade the
[74]
and were associated with the up‑regulation of endogenous growth factors and destroy granulation tissue.
VEGF. Moreover, VEGF administration improves wound
healing in nondiabetic ischemic wounds and blocking Ischemic ulcers
[75]
VEGF with neutralizing antibodies impedes tissue repair. Peripheral arterial disease (PAD) may result in severe
[76]
These studies support the notion that VEGF is critical for ischemia. Reduce tissue perfusion due to ischemia
[92]
repair in impaired healing states and that the addition results in progressive tissue hypoxia, ischemia, necrosis
of VEGF could have a potential clinical use. In fact, and skin breakdown. In theory, tissue hypoxia should
[77]
246 Plast Aesthet Res || Vol 2 || Issue 5 || Sep 15, 2015