Angiopoietins are the ligands of Tie-2 receptors and comprise four members, angiopoietin-1, -2, -3 and -4. The structure of these proteins consists of a fibrinogen (FN)-like domain responsible for Tie-2 receptor binding that contains the most conserved sequence between all angiopoietin members, a central coiled-coil domain involved in oligomerizing these FN-like domains through disulfide linkages and a short hydrophobic amino terminal domain having both secretory and superclustering functions, which thus generates variable order multimers in the interstitial space. Ang-1 was the first family member to be identified in 1996, followed by Ang-2 one year later. Although Ang-l-induced Tie-2 activation is mainly mediated by full length Ang-1 (1.5 Kb), which spans 498 amino acids (aas), three isoforms generated from alternative splicing have recently been cloned and designated as Ang-1-0.7 Kb (154 aas), Ang-1-0.9 Kb (285 aas) and Ang-1-1.3 Kb (367 aas). The roles of these isoforms are not well characterized, but recent evidence indicates that the 0.9 and 1.3 Kb isoforms, which partially lack the coiled-coiled and FN-like domains respectively, function as dominant negative regulators of full length Ang-1. Similarly, a splice variant for Ang-2, which partially lacks the coiled-coil domain and acts as a dominant negative regulator of Ang-1 has been recently characterized and designated as Ang- 2443 in humans and as Ang-2B in chickens.
Biological functions of angiopoietins during embryonic development
Targeted disruption of the Angptl gene produces similar phenotypic manifestations as those seen in TIE-2-/- mice, including gross vascular abnormalities and embryonic lethality at E l2.5. Overex
Contradictory results have thus far been obtained regarding the biological functions of Ang-2. Initial reports suggested that overex
The physiological roles of Ang-3 and Ang-4 during development are currently unknown as there are no knockout or transgenic animals of either angiopoietins, although in-vitro studies suggest that they might have similar roles in mediating angiogenesis as those of Ang-2 and Ang-1, respectively.
Angiopoietins and Tie receptors
In adults, increased Tie-2 ex
Constitutive Ang-1 ex
Tie-1 has also been implicated in modulating adult vascular functions. Recent evidence suggests that both Tie-1 and Tie-2 collaborate to reendothelize the vasculature following balloon carotid injury in the rat and to promote postnatal bone marrow haematopoiesis (387;388). Whether these effects are modulated by Ang-1, however, are unknown.
Ang-2 appears to mainly have a role during postnatal angiogenesis, particularly at sites of vascular remodeling, since Ang-2 mRNA is expressed in the placenta, uterus and ovaries of adult mammals. In addition, persistent and elevated Ang-2 ex
In adults, the similar level of activation of Tie-2 receptors by Ang-3 and Ang-4 as compared with Ang-2 and Ang-1, respectively, implies similar functions. However, the roles of Ang-3 and Ang-4 during adult physiological and pathological angiogenesis are not as well characterized as for Ang-1 and Ang-2. Ang-3 has recently been shown to inhibit tumor angiogenesis, presumably by promoting tumor cell apoptosis and inhibiting EC proliferation and survival. These effects of Ang-3 are partly mediated by antagonizing Ang-1 and VEGF signaling. Another study demonstrated that Ang-4 levels are downregulated in a murine model of LPS-induced acute lung injury, where VEGF levels are simultaneously upregulated, suggesting that like Ang-1, Ang-4 attenuates VEGF-induced inflammation. It should be pointed out, however, that the authors used an Ang-4 antibody on mice tissue, indicating they were most likely detecting Ang-3.