98 Lymphology 37

98 Lymphology 37 (2004) 98-106 Children's Hospital, Pediatrics I, Gottingen, Germany ABSTRACT function has become overruled by the nutritive function in blood vessels of larger animals. It has generally been accepted that the The circular movement of cells is driven by a blood vascular system is primary and the blood heart, which, however, is not an unique lymphatic vascular system secondary. Diseases organ. Lymph hearts are present in lower of the blood vascular system are the leading vertebrates, still develop transiently in birds, cause for mortality and morbidity in developed and are vestigial in the contractile lymphangion nations. In contrast, lymphedema is seldom which "circulates" immune cells. We conclude life-threatening and can generally be well that the definitive lymphatics are perhaps managed by combined physiotherapy. During secondary in mammals, but the blood vascular ontogeny, the blood vessels and the heart system seems to develop on the basis of an develop much earlier than the lymphatic ancestral lymphatic system with lymph hearts. vessels. However, there is growing evidence that the first vascular system occurring during DEVELOPMENT OF THE VASCULAR ontogeny and phylogeny has lymphatic SYSTEM: TRADITIONAL VIEW functions. Defense mechanisms are crucial for all organisms irrespective of their size. The blood vascular system and Macrophages precede the emergence of circulation has been in the focus of scientific erythrocytes during ontogeny, and their research ever since its discovery by William circulation in the hemolymphatic (more Harvey (1). On the other hand, the lymphatic accurately, lymphohematic) system of insects, system has mostly been neglected although which do not possess erythrocytes, shows the lymphatic vessels were discovered by that the lymphatic function is primary Gasparo Aselli (2) at almost the same time. whereas the nutritive function is secondary, The predominant interest in the blood needed only in larger organisms. In molluscs circulation compared to the lymph circulation and arthropods, which have an open vascular is obviously due to its anatomic prominence system, hemocyanin has both oxygen trans and accessibility, critical nature of its porting and defense functions. In vertebrates, functions, and the dramatic manifestations of the early blood vessels have structural its disorders as the leading cause for death in characteristics of lymphatics and express the industrialized nations. Diseases of the lymphendothelial receptor flt-4 (Vascular lymphatic vessels are disfiguring; produce Endothelial Growth Factor Receptor-3). swelling, scarring and immune dysregulation, Later, flt-4 becomes restricted to the definitive but are rarely lethal. The dense vasculari lymphatics, which are either formed from the zation of tumors has been recognized even by primary vessels or from mesodermal Rudolf Virchow (3), and the intense tumor lymphangioblasts. The primary lymphatic angiogenesis research of recent years is Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY . 99 mainly based on studies by Judah Folkman well as cell-cell and cell-matrix interactions. (4). Accordingly, the terms vasculogenesis Among them are endothelial and endocardial and angiogenesis have almost without growth factors and receptors such as exception been used in the sense of hemangio Vascular Endothelial Growth Factors genesis (and blood vessel development and (VEGFs), their receptors (VEGFR-1,-2,-3; growth). Tumor-induced lymphangiogenesis called flt-1, flk-lIKDR and flt-4, respectively) has been neglected, even denied, but clear and co-receptors, the neuropilins (13, 14). experimental evidence for this phenomenon The angiopoietins and their receptor, Tie2, as has been published recently (5,6). The proper well as the orphan receptor Tiel are of identification of lymphatic endothelial cells critical importance for embryonic hemangio (LEes) in histological sections has been genesis (15), and, additionally, members of problematic, and only in the last few years the ephrin ligand/Eph receptor family are have molecules been identified, which allow needed for blood vessel formation (16). Mice for more specific immunohistochemical with a deletion for vascular endothelial (VE) staining of LEes (review: 7). There is not only cadherin die of vascular abnormalities (17), a predominance of hemangiogenesis research and the same is true for mice that lack over lymphangiogenesis research, there extracellular matrix molecules that are also is the generally accepted view that blood critical for angiogenesis, such as fibronectin vessels are primary and lymphatic vessels (review: 18). Abnormalities of the development secondary or an offshoot of blood vessels. of the lymphatic vessels are not embryonic According to the biogenetic law of Ernst lethal. Aplasia of lymphatic vessels is only Haeckel, ontogeny is a recapitulation of found in severe genetic aberrations. phylogeny. During ontogeny, the circulatory Hypoplasia of lymphatics is found in children system develops much earlier than the suffering from the N onne-Milroy disease, and lymphatic vascular system. In the chick, the in some of the families, the inherited defect is first blood vessels can be seen after one day of a monoallelic mutation of the VEGFR-3 gene incubation (8), whereas morphological (review: 19). Mice lacking the transcription evidence for LEes is present around day 5 factor Proxl have normal blood vessels but (9). In the mouse, blood vessel development lack lymphatics (11). These mice die around starts at day 7.5 (to); the anlagen of the embryonic day 14.5, but this seems to be due lymphatics can be seen in the jugular region to the abnormal liver development. Therefore, at day 10 (11). In the human, jugular lymph there are many essential genes that control sacs have been found in 6- to 7-week-old cardiovascular development, whereas embryos of 10-14 mm total length (12). This development of lymphatics seems to be rather is 3 to 4 weeks after the development of the unproblematic and disturbed only in severe first blood vessels. In sum, these findings genetic aberrations. seem to show that the blood vascular system Has nature created the highly problematic is primary. Lymphatic vessels occur much blood vascular system first, and only later later and are therefore secondary. developed a lymphatic system, which usually The nutritive function of the circulatory does not produce any serious developmental system is crucial for the development of problems? Is it compatible with the genesis of vertebrates. Therefore, any mutation that higher organisms to produce a highly critical affects the functionality of the cardiovascular organ system out of zero, when almost every system causes early embryonic death. failure will be lethal? Wouldn't it be, from a Numerous genes with essential functions for teleological point of view, much more the development of the circulatory system appropriate to make a critical developmental have been identified. These genes code for step on the basis of an already existing molecules that regulate cell proliferation as foundation? Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY . 100 NUTRITIVE OR IMMUNE FUNCTION: adipose body (liver-homologue) in the WHAT COMES FIRST? production of anti-microbial proteins. This shows that Drosophila has a well-elaborated It is generally assumed that the need for innate immune system. The cardiovascular nutrition of all parts of the body has been the system of Drosophila ensures rapid driving force for the evolution of the cardio circulation of immune cells through the body. vascular system. However, there is an By this means the cells are able to infiltrate a excellent reason for its development even in diseased body compartment much faster than small animals where nutrition is still by would be the case by migration through the diffusion: this reason is immune defense. interstitium only. As in vertebrates, where In fact, both phylogenetically and ontogene lymph is composed of interstitial fluid and tically, defense mechanisms develop earlier immune cells, the circulatory system of than the nutritive elements of the blood. In Drosophila and other insects has all the Drosophila, supply with oxygen is typical characteristics of a lymphatic system. accomplished by an elaborate system of fine In some invertebrates, this lymphatic system channels, the tracheal system. Red blood cells takes over an additional function, a nutritive are not present, and the open hemolymphatic one. Oxygen transporting molecules system fulfils functions which are typical comparable to hemoglobin (arylphorin, lymphatic functions. The heart is connected hemocyanin) are present in various insects, to open-ended vessels and pumps interstitial arthropods and molluscs (22), but these fluid and immune cells through the body. molecules still have an additional defense It is therefore more appropriate to call this function. In crustaceans, infection induces the system a lymphohematic or lymphatic cleavage of hemocyanin into antibiotic system. Three types of immune cells are peptides (23). In cephalopods, hemocyanin found in Drosophila: plasmatocytes, crystal binds to various particles and seems to act cells and lamellocytes (20). Plasmatocytes, like an opsonizing agent, which increases the which are capable of phagocytosis, are activity of phagocytes (24). This shows that comparable to the monocyte/macrophage

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