Challenges for imaging angiogenesis.

Angiogenesis, the sprouting of new capillaries from existing blood vessels, and vasculogenesis, the de novo generation of blood vessels, are the two primary methods of vascular expansion by which nutrient supply to tissues is adjusted to match physiological demand. Accordingly, vasculogenesis is an integral and essential component of embryonic development, and angiogenesis accompanies organ growth and regeneration [1]. Angiogenesis also occurs during wound repair, in spontaneous growth of collateral vessels in response to ischaemia, in the ovaries and uterus during the female reproductive cycle, in retinopathy and in cancer. The angiogenic process is a complex multistep phenomenon involving many growth factors and interactions between a number of cell types [2]. Angiogenesis is invoked by expression of pro-angiogenic growth factors in cells of the target tissue and by suppression of anti-angiogenic factors. Expression of angiogenic growth factors can be induced as a response to hypoxic stress, by hormonal stimulation, but can also result from activation of oncogenes. Normal vessels activated by vascular endothelial growth factor (VEGF) respond within minutes by dilation and increased permeability to macromolecular serum proteins. Extravasation of plasma proteins leads to deposition of a provisional extracellular matrix (ECM), which facilitates endothelial cell migration. Prior to endothelial proliferation and migration, activated vessels show local shedding of pericytes and smooth muscle cells. These perivascular cells are essential for maintaining vascular integrity but also further suppress endothelial cell proliferation. Proliferation, migration and elongation of endothelial capillaries require degradation of the ECM, and endothelial cells thus activated release a number of proteolytic enzymes, including collagenase. Tumours may benefit from the ECM remodelling and growth factors released during the early stages of angiogenesis, even in the absence of increased perfusion [3]. This process leads to the generation of a functional but immature endothelial plexus. The final stages of angiogenesis include stabilization, remodelling and maturation of the new vessels by recruitment of pericytes and smooth muscle cells.