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Endoglin and activin receptor-like kinase 1 heterozygous mice have a distinct pulmonary and hepatic angiogenic profile and response to anti-VEGF treatment

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Abstract

Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia associated with dysregulated angiogenesis and arteriovascular malformations. The disease is caused by mutations in endoglin (ENG; HHT1) or activin receptor-like kinase 1 (ALK1; HHT2) genes, coding for transforming growth factor β (TGF-β) superfamily receptors. Vascular endothelial growth factor (VEGF) has been implicated in HHT and beneficial effects of anti-VEGF treatment were recently reported in HHT patients. To investigate the systemic angiogenic phenotype of Endoglin and Alk1 mutant mice and their response to anti-VEGF therapy, we assessed microvessel density (MVD) in multiple organs after treatment with an antibody to mouse VEGF or vehicle. Lungs were the only organ showing an angiogenic defect, with reduced peripheral MVD and secondary right ventricular hypertrophy (RVH), yet distinctly associated with a fourfold increase in thrombospondin-1 (TSP-1) in Eng +/− versus a rise in angiopoietin-2 (Ang-2) in Alk1 +/− mice. Anti-VEGF treatment did reduce lung VEGF levels but interestingly, led to an increase in peripheral pulmonary MVD and attenuation of RVH; it also normalized TSP-1 and Ang-2 expression. Hepatic MVD, unaffected in mutant mice, was reduced by anti-VEGF therapy in heterozygous and wild type mice, indicating a liver-specific effect of treatment. Contrast-enhanced micro-ultrasound demonstrated a reduction in hepatic microvascular perfusion after anti-VEGF treatment only in Eng +/− mice. Our findings indicate that the mechanisms responsible for the angiogenic imbalance and the response to anti-VEGF therapy differ between Eng and Alk1 heterozygous mice and raise the need for systemic monitoring of anti-angiogenic therapy effects in HHT patients.

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Acknowledgments

We thank Genentech for kindly providing the G6-31 anti-VEGF mouse antibody; Dr. Lee Adamson (University of Toronto) for providing the blood pressure measurement instrument and software; Lily Morikawa, MLT Manager, Pathology Core Centre from Modeling Human Disease Toronto Centre for Phenogenomics (TCP) for expert design of the hepatic and cardiac computerized protocols; Qiang Xu and Napoleon Law (CMHD Pathology Core, TCP, Toronto) for expert computerized measurements of the cardiac and hepatic MVD and for CD31 staining, respectively; Dr. Susan Newbigging (Director, CMHD Pathology Core, Toronto Center for Phenogenomics, Toronto) for facilitating the usage of the Visiopharm Integrator System; Dr. Herman Yeger, for the use of the Olympus microscope; Clinton Hupper (VisualSonics, Toronto) for performing the pilot hepatic ultrasound measurements. We thank Dr. S. Paul Oh, University of Florida, for providing the Alk1 heterozygous mice. This work was supported by grants from the Canadian Institute of Health Research (CIHR) (MOP-6247) and the Heart and Stroke Foundation of Canada to ML (T5598), and from the Terry Fox Foundation, Visual Sonics Inc. and CIHR (MOP–12164) to FSF. D. Ardelean is the recipient of a CIHR/CAG/Abbott fellowship award.

Conflict of interest

Dr. Foster discloses that he is a consultant to VisualSonics Inc. The other authors declared no conflicts of interest.

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Authors and Affiliations

  1. Molecular Structure and Function Program, Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada

    Daniela S. Ardelean, Mirjana Jerkic, Madonna Peter & Michelle Letarte

  2. Division of Rheumatology, The Hospital for Sick Children, Toronto, Canada

    Daniela S. Ardelean

  3. Department of Immunology, University of Toronto, Toronto, Canada

    Daniela S. Ardelean, Madonna Peter & Michelle Letarte

  4. Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada

    Mirjana Jerkic & Michelle Letarte

  5. Biological Sciences, Sunnybrook Health Sciences Center, Toronto, Canada

    Melissa Yin, Robert S. Kerbel & F. Stuart Foster

  6. Division of Pathology, Hospital for Sick Children, Toronto, Canada

    Bo Ngan

  7. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

    Bo Ngan

  8. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    Robert S. Kerbel, F. Stuart Foster & Michelle Letarte

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  1. Daniela S. Ardelean
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Ardelean, D.S., Jerkic, M., Yin, M. et al. Endoglin and activin receptor-like kinase 1 heterozygous mice have a distinct pulmonary and hepatic angiogenic profile and response to anti-VEGF treatment. Angiogenesis 17, 129–146 (2014). https://doi.org/10.1007/s10456-013-9383-4

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