Abstract
ApoA-1 binding protein (AIBP), a highly evolutionary conserved protein, plays a vital role in zebrafish angiogenesis, but its role of angiogenesis in higher vertebrate has not been studied. We thus propose that the role of AIBP in angiogenesis is also conserved from zebrafish to mice to humans. Since mouse models display tremendous power in the study of human cardiovascular disease as the murine and human vasculatures are highly similar. Therefore, we generated Apoa1bp -/- mice, which are viable and fertile. We then compared retinal vasculature development in Apoa1bp -/- mice and wild-type mice by whole mount immunostaining. Our data show that AIBP deficiency in mice results in significantly enhanced angiogenesis. Mechanically, We found the expressions of the Notch downstream targets Hes1 , Hey1 and Hey2 were upregulated in Apoa1bp -/- retinas compared to controls. And the protein level of Notch intracellular domain (NICD) was decreased in Apoa1bp -/- retinas. These results suggest that the activity of the Notch signaling is decreased in retinas from Apoa1bp -/- mice. Furthermore, we found AIBP affects on γ-secretase activity by enhance the colocaliztion of Notch1 and γ-secretase. Moreover, we studied whether increased HDL levels can rescue retinal angiogenesis in Apoa1bp -/- mice. We crossed ApoA1 transgenic mice with Apoa1bp -/- mice. As expected, increased HDL levels rescued dysregulated angiogenesis in Apoa1bp -/- mice, indicating that AIBP regulates angiogenesis through its effect on lipid rafts. Our study demonstrated that AIBP positively regulates the Notch signaling pathway by effect on lipid rafts, which in turn inhibits retinal angiogenesis. We are the first to connect AIBP, a cholesterol metabolism regulator, to Notch signaling.
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