Requisite Role of Angiopoietin-1, a Ligand for the TIE2 Receptor, during Embryonic Angiogenesis

Abstract

Vascular endothelial growth factor (VEGF), which acts via members of a family of endothelial-specific receptor tyrosine kinases, is the only factor that has been shown definitively to play a role in the formation of the embryonic vasculature. Only one other family of receptor tyrosine kinases, comprising TIE1 and TIE2, is largely endothelial cell specific. We have recently cloned a ligand for TIE2, termed Angiopoietin-1. Here we show that mice engineered to lack Angiopoietin-1 display angiogenic deficits reminiscent of those previously seen in mice lacking TIE2, demonstrating that Angiopoietin-1 is a primary physiologic ligand for TIE2 and that it has critical in vivo angiogenic actions that are distinct from VEGF and that are not reflected in the classic in vitro assays used to characterize VEGF. Angiopoietin-1 seems to play a crucial role in mediating reciprocal interactions between the endothelium and surrounding matrix and mesenchyme.

Cotargeting of VEGFR-1 and -3 and angiopoietin receptor Tie2 reduces the growth of solid human ovarian cancer in mice

“…15 Angiopoietins (Ang1-4) are ligands for the tyrosine kinase receptor Tie2. [16][17][18] Ang1 activates Tie2 signaling pathways and promotes the recruitment of pericytes and smooth muscle cells to the developing vessels 16,19 and contributes to tumor dissemination and metastasis. 20 Ang2, on the contrary, functions in a context-dependent manner as an antagonist promoting either blood vessel growth or regression depending on the levels of other growth factors, such as VEGF-A.…”

The enigmatic role of angiopoietin-1 in tumor angiogenesis

“…Although Ang1 does not stimulate proliferation of endothelial cells [18], in vitro Ang1 can induce endothelial migration [22], tubule formation [23] and sprouting [24,25], and survival from a variety of apoptotic insults [26][27][28][29], suggesting that Ang1 can be a potent pro-angiogenic factor. Transgenic null mutation of the Ang1 gene confirms an angiogenic role for Ang1, as Ang1 null embryos are unable to form a complex vascular network and exhibit decreased vessel support by mural cells [19]. These results gave the first indication that Ang1 may play a role in recruitment of mural cells to support the primitive endothelial tubule and enhance vessel maturation.…”

“…The Angiopoietin family of growth factors is comprised of four family members that bind to the Tie2 tyrosine kinase receptor with different outcomes. Angiopoietin-1 (Ang1), the main ligand for Tie2 [18,19], and -4 [20] are agonistic ligands, whereas Angiopoietin-2 (Ang2) and -3 can serve as antagonistic ligands [20,21]. Although Ang1 does not stimulate proliferation of endothelial cells [18], in vitro Ang1 can induce endothelial migration [22], tubule formation [23] and sprouting [24,25], and survival from a variety of apoptotic insults [26][27][28][29], suggesting that Ang1 can be a potent pro-angiogenic factor.…”

“…Tumor vessels in the Ang1-transfected breast [50], colon [69], hepatic colon tumor [88], and squamous cell [77] xenografts mentioned above all demonstrate significantly increased association of pericytes with vessels, suggesting that enforced maturation of blood vessels may functionally inhibit tumor angiogenesis. First of all, the ability of Ang1 to inhibit vascular permeability is thought to be due partly to the enhancement of cell-cell junctions [40], as well stabilization of blood vessels by the promotion of mural cell recruitment [19,34,35,38]; it is interesting to note that the absence of pericytes leads to defects in endothelial junction formation [16]. In addition, peripheral blood vessels in the Ang1-transfected MCF7 tumors were not dilated, in contrast to those in the vector control counterparts [50].…”

Blood–Brain Barrier Disruption, Vascular Impairment, and Ischemia/Reperfusion Damage in Diabetic Stroke

“…Ang‐1 promotes vascular maturation and stabilization as well as in increases angiogenesis after stroke 69. Ang‐1 is a primary physiological ligand for TIE2 and plays a vital role in the migration, adhesion, and survival of endothelial cells and in vessel maturation 70. Ang‐1 regulates the organization and maturation of new blood vessels, and decreases leakage and endothelial death 71.…”