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Theranostics 2015; 5(2):206-217. doi:10.7150/thno.9847 This issue Cite

Research Paper

Ultrasound Molecular Imaging of Vascular Endothelial Growth Factor Receptor 2 Expression for Endometrial Receptivity Evaluation

Hongmei Liu^{1, 2 *}, Yihan Chen^{1, 2 *}, Fei Yan^{1, 3, 4✉}, Xiaohua Han¹, Junru Wu⁵, Xin Liu³, Hairong Zheng^{1, 3, 6✉}

1. Department of Ultrasonography, The Third Affiliated Hospital of Southern Medical University, Guagnzhou, China;
2. Institute of Musculoskeletal Medical Imaging, Academy of Orthopaedics in Guangdong Province, Guagnzhou, China;
3. Paul C. Lauterbur Research Center for Biomedical Imaging, Institute of biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China;
4. Shenzhen Key Laboratory for Molecular Imaging, Shenzhen, China.
5. Department of Physics, University of Vermont, Burlington, VT, USA.
6. Shenzhen Key Laboratory of Nanobiomechanics, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
*Both authors contributed equally to this manuscript.

✉ Corresponding author: Fei Yan, PhD and, Hairong Zheng PhD, 1068 Xueyuan Avenue, Shenzhen University Town, Shenzhen, P.R. China 518055, E-mails: fei.yanac.cn and hr.zhengac.cn. Telephone: +86 755 86392284, Fax: +86 755 96382299.

Abstract

Purpose: Ultrasound (US) molecular imaging by examining the expression of vascular endothelial growth factor receptor 2 (VEGFR2) on uterus vascular endothelium was applied to evaluate the endometrial receptivity.

Methods: VEGFR2-targeted ultrasound contrast agents (UCA) and the control UCA (without VEGFR2) were prepared and characterized. Adhesion experiment in vitro was performed with mouse microvascular endothelial cells (bEnd.3) and the ratio of the number of UCA to that of cells at the same field was compared. In vivo study, randomized boluses of targeted or control UCA were injected into the animals of non-pregnancy (D0), pregnancy on day 2 (D2) and day 4 (D4), respectively. Sonograms were acquired by an ultrasound equipment with a 40-MHz high-frequency transducer (Vevo 2100; VisualSonics, Toronto, Canada). The ultrasonic imaging signals were quantified as the video intensity amplitudes generated by the attachment of VEGFR2-targeted UCA. Immunoblotting and immunofluorescence assays were used for confirmation of VEGFR2 expression.

Results: Our results showed that VEGFR2-targeted UCA could bind to bEnd.3 cells with significantly higher affinity than the control UCA (9.8 ± 1.0 bubbles/cell versus 0.7 ± 0.3 bubbles/cell, P < 0.01) in vitro. The mean video intensity from the US backscattering of the retained VEGFR2-targeted UCA was significantly higher than that of the control UCA in D2 and D4 mice (D2, 10.5 ± 2.5 dB versus 1.5 ± 1.1 dB, P < 0.01; D4, 15.7 ± 4.0 dB versus 1.5 ± 1.2 dB, P < 0.01), but not significantly different in D0 mice (1.0 ± 0.8 dB versus 0.9 ± 0.6 dB, P > 0.05). Moreover, D4 mice showed the highest video intensity amplitude, indicating the highest VEGFR2 expression when compared with D2 and D0 mice (P < 0.01). This was further confirmed by our immunoblotting and immunofluorescence experiments.

Conclusion: Ultrasound molecular imaging with VEGFR2-targeted UCA may be used for noninvasive evaluation of endometrial receptivity in murine models.

Keywords: Endometrial receptivity, Ultrasound molecular imaging, Vascular endothelial growth factor receptor 2.

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