Angiogenesis, the formation of blood vessels from preexisting vessels, occurs during embryonic and adult life. 1 Although vascular endothelial cells in the normal adult organism have a very low turnover, they resume proliferation in diseases that are associated with neovascularization, such as solid tumor growth, wound healing, and retinopathy. 2 A host of recent publications has indicated that the molecules and mechanisms involved in both embryonic and adult angiogenesis are similar. 1, 3, 4 For example, neutralizing or deleting the function of vascular endothelial growth factor (VEGF) 5–7 or its receptors (VEGF-R1/flt-18, 9 and VEGF-R2/flk-1/KDR10, 11) abolished embryonic and adult blood vessel formation, including vasculogenesis, the formation of blood vessels from angioblasts in situ, 12 and adult physiological (eg, in the corpus luteum) and pathological (eg, in tumors) angiogenesis. Therefore, one could propose that adult angiogenesis merely recapitulates embryonic angiogenesis. This view is now challenged by Lee et al, 13 who, in this issue of Circulation Research, present the first evidence that adult angiogenesis may require additional factors and mechanisms. They found that Thy-1 was upregulated in newly formed blood vessels in four models of angiogenesis in adult rats, whereas it was not expressed during vasculogenesis or angiogenesis in the embryo. Notably, the four models included both pathological (tumor, balloon injury, and ligation of renal artery) and physiological (uterine vessels during pregnancy) angiogenesis. One of the conclusions from the work of Lee at al is therefore that embryonic vascular endothelium differs from adult vascular endothelium. There is precedence for differences between “young” and “old” endothelium. Adult endothelium has a low turnover, is mature (ie, has complete vascular basal lamina in most vessels and “thin” endothelium with smooth luminal and abluminal surfaces), and expresses organ-specific characteristics. 14 It is, in general, much less “plastic” than embryonic endothelium. For example, embryonic endothelium from the dorsal aorta can be transplanted into the brain and differentiate to blood-brain barrier endothelium. 15 There is also massive remodeling, pruning, and angioblast migration occurring in the embryonic vascular system that is virtually absent in the adult. The tentative proposal from these observations is that the normal adult organism has adjusted its vascular system to its need, has established it to a certain degree, and may be refractory to new blood vessel formation. 1 This concept is supported by studies on angiogenesis inhibitors. Although no molecular mechanism of action is known for angiostatin, endostatin, and thrombospondin, they all have been reported by previous studies16–18 to inhibit angiogenesis in in vivo model systems such as those used by Lee et al. 13 Coincidentally, at present, none of these inhibitors is known to play a role in embryonic angiogenesis. Mice deficient for thrombospondin and plasminogen (of which angiostatin is a fragment) display an apparently normal embryonic circulation. 19, 20 The thrombospondin-2 knockout is particularly interesting because twice as many blood vessels were counted in mutant compared with wild-type tissues. This difference was reported to be significant for adult but not for embryonic or neonatal tissue. 20 Therefore, angiogenesis inhibitors may play a role in shaping the postnatal but not the embryonic vascular system.

The second conclusion from the study of Lee et al13 is that as hypothesized earlier, 1 adult angiogenesis is accompanied by, if not dependent on, inflammation. Inflammatory cytokines (eg, tumor …