Angiotensin II Potentiates Vascular Endothelial Growth Factor–Induced Angiogenic Activity in Retinal Microcapillary Endothelial Cells

From the Department of Ophthalmology and Visual Sciences, Kyoto (Japan) University Graduate School of Medicine.

Correspondence to Hitoshi Takagi, MD, PhD, Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto 606, Japan. E-mail hitoshi{at}kuhp.kyoto-u.ac.jp

Abstract

Abstract—Angiotensin II (Ang II) plays a role in the development of many vascular diseases. In the present study, we have investigated the effect of Ang II on vascular endothelial growth factor (VEGF) receptor expression and VEGF-induced angiogenic activity in bovine retinal microcapillary endothelial cells (BRECs). Ang II induced a significant increase of kinase domain–containing receptor/total liver kinase (KDR/Flk-1) mRNA in a time- and dose-dependent manner, with a maximal 4.3±0.8-fold increase after a 4-hour stimulation. Ang II increased the rate of KDR gene transcription by 5.4-fold, whereas the half-life of KDR mRNA was not increased significantly. The increase depended partially on new protein synthesis. The Ang II–induced KDR mRNA increase was inhibited by either [Sar¹,Ile⁸]angiotensin or angiotensin type 1 receptor antagonists but was not significantly altered by angiotensin type 2 receptor antagonists. The PKC inhibitor reduced Ang II–induced KDR mRNA expression by 70±15%. The tyrosine kinase inhibitor reduced the Ang II– and phorbol 12-myristate 13-acetate–induced KDR mRNA increases by 35±8% and 44±26%, respectively. Ang II increased by 3.1-fold the ³⁵S-labeled KDR/Flk-1 immunoprecipitated by a specific antibody to KDR/Flk-1. Scatchard analysis demonstrated that Ang II induced a significant increase of binding sites without changing binding affinity. Ang II enhanced VEGF-induced cell growth and tube formation. Ang II itself had no effect on cell growth, tube formation, or mRNA levels of VEGF and tms-like tyrosine kinase (Flt-1) in BRECs. These findings suggest that Ang II might potentiate VEGF-induced angiogenic activity through an increase of the VEGF receptor KDR/Flk-1.

Key Words: diabetic retinopathy • vascular endothelial growth factor • KDR/Flk-1 • angiotensin II • angiogenesis

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