The Science behind Our Technology - Angiogenesis
Blood vessels that make up the cardiovascular system may be broadly divided into arteries, veins and capillaries. Arteries carry blood away from the heart at relatively high pressure; veins carry blood back to the heart at low pressure, while capillaries provide the link between the arterial and venous blood supply. During embryonic development, vessels are first formed through vasculogenesis, utilizing pluripotent endothelial cell precursors. Later, through arteriogenesis, larger blood vessels are formed possessing a more complex structure of endothelial cells, smooth muscle cells and pericytes (tunica media). Although arteriogenesis is not considered to occur in the adult, blood vessels may be formed in the adult through angiogenesis. Under normal conditions, angiogenic neovascularization occurs during such conditions as wound repair, ischemic restoration (ischemia is a restriction in blood supply generally due to factors in the blood vessels with resultant damage or dysfunction of tissue) after myocardial infarction and the female reproductive cycle (generating endometrium forming the corpus luteum and during pregnancy to create the placental).
The capillaries, relatively simple vessels formed by angiogenesis, lack a developed tunica, as they are predominantly composed of endothelial cells, perivascular cells and basement membrane. If formed aberrantly, they may induce or promote a variety of pathological conditions. For example, aberrant neovasculature is found in cancer, ocular diseases (such as macular degeneration, diabetic retinopathy and retinopathy of prematurity), arthritis and psoriasis.
Oncology
Tumors which are less than a few millimeters in size utilize nearby normal vessels to provide nutrients and oxygen. However, above this critical size, cancer cells may utilize angiogenesis to create additional vascular support. Normally, angiogenesis is kept in check by the body naturally creating angiogenic inhibitors to counteract angiogenic factors. However, the cancer cell changes this balance by producing angiogenic growth factors in excess of the angiogenic inhibitors, thus favoring blood vessel growth. Cancer cell induced angiogenesis utilizes common pathways of angiogenesis observed during normal vessel growth. Angiogenic factors pass from the cancer cell to the normal endothelium, binding the endothelial cell, activating it and inducing endothelial signaling events leading to endothelial cell proliferation. Endothelial tubes begin to form, homing in toward the tumor with the formation of capillary loops. Capillaries then undergo a maturation process to stabilize loop structure, but the resulting vessels formed tend to be leaky, structurally aberrant, inefficient and fragile.
Ophthalmology
The pathological neovasculature found in ocular diseases are formed in a manner similar to that of tumor vessels. Through a combination of inflammation, localized hypoxia by retinal capillary bed occlusion and oxidative products found in retinal exudates, angiogenic factors are secreted by the retina and induce angiogenesis not unlike that of cancer described above, also forming vessels that lack the integrity of normal vessels.
Dermatology
Skin diseases such as psoriasis and atopic dermatitis also have a pathological component of angiogenesis where vessels expand aberrantly in the dermis of the skin. In these diseases, keratinocytes may be the initiator by secreting angiogenic cytokines to induce angiogenesis. Furthermore, these same keratinocytes are in an activated state and induce their own epidermal hyperplasia. The presence of the aberrant vessels along with keratinocytes secreting factors then can facilitate accumulation of inflammatory cells, particularly T lymphocytes, monocytes and neutrophils which can further secrete skin activating factors. This creates a vicious circle where the presence of neovascularization brings in cells which facilitate their growth and the growth of keratinocytes and endothelial cells forming vessels. Again, using a similar set of cytokines as described above for both cancer and ocular disease. Hence, agents capable of inhibiting tumor, ocular or skin vasculature would be expected to show similar effects respectively in pathological neovascular diseases.
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