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. 2009 May 12;48(18):3804-6.
doi: 10.1021/bi9005094.

Ribonuclease inhibitor regulates neovascularization by human angiogenin

Kimberly A Dickson  1 , Dong-Ku Kang, Young Sam Kwon, Jae Chan Kim, Peter A Leland, Byung-Moon Kim, Soo-Ik Chang, Ronald T Raines
Affiliations

Ribonuclease inhibitor regulates neovascularization by human angiogenin

Kimberly A Dickson et al. Biochemistry. .

Abstract

Human angiogenin (ANG) is a homologue of bovine pancreatic ribonuclease (RNase A) that induces neovascularization. ANG is the only human angiogenic factor that possesses ribonucleolytic activity. To stimulate blood vessel growth, ANG must be transported to the nucleus and must retain its catalytic activity. Like other mammalian homologues of RNase A, ANG forms a femtomolar complex with the cytosolic ribonuclease inhibitor protein (RI). To determine whether RI affects ANG-induced angiogenesis, we created G85R/G86R ANG, which possesses 10(6)-fold lower affinity for RI but retains wild-type ribonucleolytic activity. The neovascularization of rabbit corneas by G85R/G86R ANG was more pronounced and more rapid than by wild-type ANG. These findings provide the first direct evidence that RI serves to regulate the biological activity of ANG in vivo.

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Figures

Figure 1
Figure 1
(A) Structure of the human RI·ANG complex (PDB entry 1a4y (16)). RI, blue; ANG, red. (B) Contacts between RI and Gly85/Gly86 of ANG within the rectangle of panel A.
Figure 2
Figure 2
Induction of angiogenesis by wild-type ANG and its G85R/G86R variant in vivo. (A) Slit-lamp photographs of representative rabbit corneas 3, 7, 10, and 14 days after implantation of a hydrogel pellet containing vehicle, wild-type ANG (10 μg), or its G85R/G86R variant (10 μg). Arrowheads, limbus; arrows, pellet; brackets, new blood vessels formed after treatment with the G85R/G86R variant. (B) Score for corneal neovascularization. Data are mean values (±SE) for 8 scores (4 eyes × 2 observers). (C) Histological photographs (×200) of rabbit corneas 14 days after pellet implantation. Arrows indicate new blood vessels. (D) Model for inhibition of the neovascularization activity of ANG by RI.
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