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2 The Cardiovascular System

During early embryogenesis, most of the blood vessels form by vasculogenesis, the in-situ formation of an immature network of endothelial channels by the differentiation of precursor cells (angioblasts). Vasculogenesis starts in extra-embryonic tissues where putative mesodermal precursor cells (hemangioblasts) aggregate into blood islands. Cells in the center of a blood island develop into hematopoietic stem cells, and cells at the periphery differentiate into angioblasts. In the embryo proper, vasculogenesis gives rise to the heart endocardium, the paired dorsal aortas and the primitive vasculature of endodermally derived organs (e.g. lung, spleen and pancreas; reviewed by Wilting and Christ 1996).

The primitive vascular network grows and remodels into a functional, hierarchical structure containing large caliber vessels for low-resistance fast flow and small capillaries optimized for diffusion. Different cellular and molecular mechanisms (splitting, fusion, sprouting, and intercalation) participate in the remodeling and expansion and they are collectively referred to as angiogenesis (reviewed by Risau 1998). While most organs become vascularized by a combination of vasculogenesis and angiogenesis, initially avascular ectodermal tissues such as the brain, become vascularized exclusively by angiogenic mechanisms (Plate 1999).

The endothelial cell layer (intima) of vessels larger than capillaries becomes wrapped by additional sheets: a cover of muscular tissue (media) and connective tissue (adventitia). Therefore, arteriogenesis requires the recruitment and organization of non-endothelial cells (reviewed by Carmeliet 2000a). Recent data shows that during embryonic development blood vessels not only fulfill transport functions but also play important roles in the induction and morphogenesis of organs (Lammert et al. 2001; Matsumoto et al. 2001). It has been thought that angiogenesis is the only way of neovascularization in adult organisms, but recently a population of progenitor cells able to differentiate into endothelial cells was isolated from circulating blood (Asahara et al. 1997) and identified as originating from bone marrow (Shi et al. 1998). Although the evidence for vasculogenesis from circulating endothelial precursors is convincing, the relative contribution of endothelial precursors to adult physiological or pathological angiogenesis is still unclear (Asahara et al. 1999; Crosby et al. 2000). In any case, there is reason to rigorously review these reports, since it has been shown that cell fusion events can produce experimental results that can be misinterpreted as differentiation events (Terada et al. 2002).

Quiescence is the default state of adult vasculature, and only few physiological processes in the adult involve endothelial cell proliferation, e.g. the female reproductive cycle (reviewed by Reynolds et al. 1992) or exercised-induced muscular hyperplasia (reviewed by Tomanek and Torry 1994). On the other hand, in disease angiogenesis frequently contributes to the pathological process (e.g. in tumorigenesis) and even may be the main pathological process itself (e.g. in wet age-related macular degeneration; reviewed by Carmeliet and Jain 2000).

Vascular endothelium is heterogeneous. Three distinct types of blood capillaries can be distinguished: continuous, fenestrated and discontinuous. Continuous endothelium has an uninterrupted basement membrane and most of the capillaries belong to this type. Fenestrated endothelium is characterized additionally by the presence of circular transcellular openings (fenestrae) with a diameter of 60 to 80 nm. Fenestrated endothelium is usually found in organs with high rates of fluid exchange (small intestine, kidney, salivary glands). Discontinuous endothelium has large intercellular gaps (up to 1 microm) and no basement membrane, and allows for almost unrestricted transport of molecules from interstitium to capillary lumen. Discontinuous endothelium is only found in specialized organs, e.g. in the liver, spleen and bone marrow (reviewed by Risau 1998).

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