In the developing embryo as well as in adult tissues, key events and distinct mechanisms exist to establish and maintain a functional vascular network (Fig. 1). Endothelial progenitor cells (EPCs) arising from various embryonic regions or from adult bone marrow can form vessels in a process referred to as vasculogenesis. Angiogenesis denotes the process in which budding from preexisting vessels gives rise to sprouts of new blood vessels, while arteriogenesis refers to the stabilisation of these new sprouts by mural cells such as pericytes and smooth muscle cells (SMCs)-arteriogenesis is critical for the new vascula-ture to become stable, mature and functional. Collateral vessel growth repre-
Table 2 Diseases characterised or caused by insufficient angiogenesis or vessel regression
Disease in mice or humans
Amyotrophic lateral sclerosis; diabetic neuropathy
Ischaemic heart disease, cardiac failure
Gastric or oral ulcerations
Vasoconstriction, microvascular degeneration and cerebral angiopathy due to EC toxicity by amyloid-p <de la Torre 20041 zloko™ 2°°5) Impaired perfusion and neuroprotection, causing motoneurone or axon degeneration due to insufficient VEGF production
(Oosthuyse et al. 2001; Lambrechts et al. 2003; Azzouz et al. 2004; Storkebaum and Carmeliet 2004; Storkebaum et al. 2005)
Correlation of survival with angiogenesis in brain (KruPlnskl et aL 1994); stroke due to arteriopathy (Notch-3 mutations (Kalimo et aL 2002)) Characterised by impaired collateral growth (Waltenberger 2001) and angiogenesis in ischaemic limbs (Rlvardet al-19"); but enhanced retinal neovascularisation secondary to pericyte drop-out (Caldwe11 et aL 2005) Microvessel rarefaction due to impaired vasodilatation or angiogenesis
(Boudier 1999; Kubis et al. 2002; Sane et al. 2004)
Characterised by impaired collateral vessel development(Van Belle et aL 1997) Impaired re-endothelialisation after arterial injury (Gennaro et aI- 2003i Imbalance in capillary-to-cardiomyocyte fibre ratio due to reduced VEGF
levels Oesminet al. 2005; Shiojima et al. 2005)
Delayed healing due to production of angiogenesis inhibitors by pathogens (H pylori) 0enkinson et al- 2002' Kim et al- 2004)
Characterised by mucosal ischaemia(Konno et aL 2004; Hatoum et aL 2005'
Table 2 (continued)
Disease in mice or humans
Osteoporosis, impaired bone fracture healing
Menorrhagia (uterine bleeding) Neonatal respiratory distress syndrome (RDS)
Pulmonary fibrosis, emphysema
Nephropathy (ageing; metabolic syndrome); glomerulosclerosis; tubulointerstitial fibrosis
Impaired bone formation due to age-dependent decline of VEGF-driven angiogenesis (Martmez et aL 2002). angiogenesis inhibitors prevent fracture healing <Yin et aL 2002>; osteoporosis due to low VEGF <Pufe et aL 2003>; healing of fracture non-union is impaired by insufficient angiogenesis (Hausman and Rinker 2004)
Retarded hair growth by angiogenesis inhibitors 'Yano et aL 2001' Age-dependent reduction of vessel number and maturation (SMC drop-out) due to EC telomere shortening (chanset aL 2002) Insufficient compensatory angiogenic response (Mackiewicz et at. 2002) EC dysfunction, resulting in organ failure, thrombosis and hypertension due to deprivation of VEGF by soluble Fltl <Maynard et aL 2003;Levine et aL 2004> Fragility of SMC-poor vessels due to low Ang-1 production (Hewett et aL 2002) Insufficient lung maturation and surfactant production in premature mice with low HIF-2/VEGF (Compernoiie et al. 2002). low yEGF levels in human neonates also correlate with RDS (Tsao et aL 2005> Alveolar EC apoptosis upon VEGF inhibition
(Kasahara et al. 2000; Tang et al. 2004b; McGrath-Morrow et al. 2005)
Characterised by vessel dropout, microvasculopathy and EC dysfunction (low VEGF' high TSP1) ' Kang et al. 2001; Gealekman et al. 2004; Long et al. 2005).
recovery of glomerular/peritubular ECs in glomerulonephritis, thrombotic microangiopathy and nephrotoxicity is VEGF-dependent (Schrlivers et al- 2004)
Fig. 1 a-c Mechanism of vessel growth. a Angiogenesis denotes the sprouting of new endothelial cell-lined vessels from pre-existing vessels; arteriogenesis refers to the subsequent stabilisation of nascent vessels via recruitment of smooth muscle cells. b Vasculogenesis refers to the recruitment of bone marrow-derived endothelial progenitors, which are incorporated into nascent vessels or stimulate new vessel growth by releasing pro-angiogenic factors. c Collateral vessel growth denotes the expansive growth of pre-existing collateral vessels upon occlusion of a supply vessel, for instance by a thrombus. Recruitment of macrophages and monocytes to the shear stress-activated endothelium plays a critical role in this process
Fig. 1 a-c Mechanism of vessel growth. a Angiogenesis denotes the sprouting of new endothelial cell-lined vessels from pre-existing vessels; arteriogenesis refers to the subsequent stabilisation of nascent vessels via recruitment of smooth muscle cells. b Vasculogenesis refers to the recruitment of bone marrow-derived endothelial progenitors, which are incorporated into nascent vessels or stimulate new vessel growth by releasing pro-angiogenic factors. c Collateral vessel growth denotes the expansive growth of pre-existing collateral vessels upon occlusion of a supply vessel, for instance by a thrombus. Recruitment of macrophages and monocytes to the shear stress-activated endothelium plays a critical role in this process sents the formation of collateral bridges between arterial networks and remodelling of pre-existing vessels after occlusion of a main artery-this type of vessel growth is of major therapeutic importance. A fine-tuned interplay between molecular signals in a spatial and temporal manner is necessary for these essential events to occur. We will now discuss these individual steps in more detail.
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