Mechanisms of Angiogenesis and Arteriogenesis
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© 2000 Nature America Inc. • http://medicine.nature.com REVIEW Endothelial and smooth muscle cells interact with each other to form new blood vessels. In this review, the cellular and molecular mechanisms underlying the formation of endothelium-lined channels (angiogenesis) and their maturation via recruitment of smooth muscle cells (arteriogenesis) during physiological and pathological conditions are summarized, alongside with possible therapeutic applications. Mechanisms of angiogenesis and arteriogenesis Normal tissue function depends on ade- sels in diabetic patients causes aneurys- quate supply of oxygen through blood PETER CARMELIET mal dilatation, bleeding and blindness. vessels. Understanding how blood ves- During the subsequent arteriogenesis, sels form has become a principal, yet challenging, objective of vessels become covered by a muscular coat, thereby endowing the last decade. Unraveling these mechanisms would offer blood vessels with viscoelastic and vasomotor properties, nec- therapeutic options to ameliorate or perhaps even cure disor- essary to accommodate the changing needs in tissue perfusion ders that are now leading causes of mortality. In this mille- (Fig. 1). Periendothelial cells also assist endothelial cells in ac- nium, we will be required to answer such questions as: Will it quiring specialized functions in different vascular beds3. be possible to treat ischemic heart disease by stimulating my- Arteriogenesis is recapitulated during the pathological enlarge- ocardial angiogenesis, and will it be feasible to cure cancer or ment of preexisting collateral vessels (Fig. 2). Therefore, strate- inflammatory disorders by suppressing excessive vessel gies to promote sustainable and functional new blood vessels growth? Unfortunately, research on angiogenesis has for too should not be restricted to the induction of capillary angio- long remained descriptive, mainly because the molecular ‘play- genesis, but should include the stimulation of arteriogenesis. .com ers’ were not identified. The recent discovery of candidates able Likewise, the therapeutic regression of ‘muscularized’ vessels to stimulate or inhibit endothelial cells has stirred a growing may require strategies other than the inhibition of endothe- .nature interest in using these molecules for therapeutic applications. lium-lined vessels. This overview provides an update on the present understand- ing of the basic molecular mechanisms of how endothelial and Vasculogenesis: the formation of a primitive network smooth muscle cells interact with each other to form blood ves- Endothelial and hematopoietic cells share a common progen- sels, as a basis for design of future (anti)-angiogenic treatments. itor (the hemangioblast). In the yolk sac, hemangioblasts form aggregates in which the inner cells develop into http://medicine • Development of an endothelium-lined vasculature hematopoietic precursors and the outer population into en- Blood vessels in the embryo form through vasculogenesis; that dothelial cells (Fig. 1). Angioblasts may migrate extensively is, through in situ differentiation of undifferentiated precursor before in situ differentiation and plexus formation. Vascular cells (angioblasts) to endothelial cells that assemble into a vas- endothelial growth factor (VEGF), VEGF receptor (VEGFR) 2 cular labyrinth1 (Fig. 1). Historically, the term angiogenesis was and basic fibroblast growth factor (bFGF) influence angioblast first used to describe the growth of endothelial sprouts from differentiation4–7, whereas VEGFR1 suppresses hemangioblast preexisting postcapillary venules (Fig. 1). More recently, this commitment8. The molecular mechanisms of how transform- term has been used to generally denote the growth and remod- ing growth factor (TGF)-β1 and TGF-β receptor 2 affect vascu- eling process of the primitive network into a complex network. logenesis remain mostly undetermined9. Molecules mediating 2000 Nature America Inc. This involves the enlargement of venules, which sprout or be- interactions between endothelial cells and matrix macromol- © α come divided by pillars of periendothelial cells (intussuscep- ecules, fibronectin or matrix receptors ( 5 integrin), also affect α β tion) or by transendothelial cell bridges, which then split into vasculogenesis. The v 3 integrin mediates vasculogenesis in individual capillaries (Fig. 1). New vessels in the adult arise avian but not in murine embryo10. mainly through angiogenesis, although vasculogenesis also Little is known about the mechanisms governing endothe- may occur (Fig. 2). Because vasculogenesis only leads to an im- lial cell fate: Ets-1, Hex, Vezf1, Hox and GATA family members, mature, poorly functional vasculature, angiogenesis is a thera- basic helix–loop–helix factors and their inhibitors of differen- peutic goal. As the cellular and molecular mechanisms of tiation may be involved11. Such molecules may be of thera- angiogenesis differ in various tissues (vessels in psoriatic skin peutic value, as they could determine the ‘decision’ of enlarge, but they sprout in ischemic retina), the therapeutic endothelial cells to become angiogenic during pathological stimulation or inhibition of angiogenesis should be adjusted to conditions (called ‘angiogenic switch’)12. The fate of endothe- the target tissue. lial cells to become integrated into arteries or veins is medi- ated by the bHLH transcription factor gridlock at the Smooth muscle–endothelial cell interactions angioblast stage, and, subsequently, by members of the Although endothelial cells have attracted most attention, they ephrin family, signals that are also involved in guidance of alone can initiate, but not complete, angiogenesis; perien- axons and repulsion of neurons14. It was once believed that dothelial cells are essential for vascular maturation (Fig. 3). endothelial precursors only exist during embryonic life. During ‘vasular myogenesis’, mural cells stabilize nascent ves- However, endothelial precursor cells have been identified in sels by inhibiting endothelial proliferation and migration, and bone marrow and in peripheral blood in adults. VEGF, granu- by stimulating production of extracellular matrix (Fig. 1). locyte–monocyte colony-stimulating factor, bFGF and in- They thereby provide hemostatic control and protect new en- sulin-like growth factor (IGF)-1 stimulate their differentiation dothelium-lined vessels against rupture or regression. Indeed, and mobilization15,16. Such precursors colonize angiogenic vessels regress more easily as long as they are not covered by sites and vascular prostheses in the adult and may hold smooth muscle cells2; the loss of pericytes around retinal ves- promise for future therapy (Fig. 2). NATURE MEDICINE • VOLUME 6 • NUMBER 3 • MARCH 2000 389 © 2000 Nature America Inc. • http://medicine.nature.com REVIEW of the u-PA receptor inhibit tumor angiogenesis. MMP-3, MMP-7 and MMP-9 affect angiogenesis in neonatal bones22 and tumors23, whereas tissue inhibitors of MMPs 1 or 3) or PEX, the naturally oc- curring fragment of MMP-2, by preventing binding of α β MMP-2 to v 3, inhibit tumor angiogenesis24. Paradoxically, tissue inhibitor of MMPs 1 and plasminogen activator- inhibitor 1 are risk factors for a poor prognosis in cancer patients and promote tumor angiogenesis in mice by preventing excessive proteoly- sis (Bajou et al, manuscript submitted)23. In support of this, endostatin inhibits Fig. 1 Endothelial precursors (angioblasts) in the embryo assemble in a primitive network (vasculogenesis), .com that expands and remodels (angiogenesis). Smooth muscle cells cover endothelial cells during vascular myoge- tumor angiogenesis by increas- nesis, and stabilize vessels during arteriogenesis. CL: collagen; EL: elastin; Fib: fibrillin (Fib). ing plasmin generation (A. .nature Reijerkerk et al., manuscript submitted). Angiogenesis: sprouting and remodeling Endothelial cell proliferation and migration: Once the path has Angiogenic sprouting is one, but not the only, mechanism of been cleared, proliferating endothelial cells migrate to distant blood vessel formation in the adult; however, it has been stud- sites. VEGF (ref. 4), placental growth factor (PLGF), VEGF-B, ied most extensively. The molecular basis of angiogenesis in VEGF-C, VEGF-D and their receptors VEGFR2, VEGFR3 (ref. 25) http://medicine • the embryo seems to differ from that of pathological angiogen- and neuropilin-1 (a co-receptor of VEGFR2; ref. 26) have specific esis in the adult (Figs. 1 and 2). Several steps have been deter- functions: VEGF and its receptor VEGFR2 affect embryonic, mined (Fig. 3). neonatal and pathological angiogenesis and are therapeutic tar- Vasodilation, endothelial permeability and periendothelial gets, although much remains to be learned about the involve- support: Angiogenesis initiates with vasodilation, a process in- ment of the distinct VEGF isoforms or of the heterodimers of 4–6,27 volving nitric oxide (Fig. 1). Vascular permeability increases VEGF family members . VEGF120 alone initiates but does not in response to VEGF, thereby allowing extravasation of complete angiogenesis28. VEGFR3 is involved in embryonic an- plasma proteins that lay down a provisional scaffold for mi- giogenesis29 and is expressed in pathological angiogenesis, grating endothelial cells. This increase in permeability is me- whereas VEGF-C (a ligand of VEGFR3) is angiogenic in adult 2000 Nature America Inc. 30 diated by the formation of fenestrations, vesiculo–vacuolar pathology . The angiogenic or lymphangiogenic activity of ©