Endoglin and activin receptorlike kinase 1 hetero

Authors: Daniela S Ardelean Mirjana Jerkic Melissa Yin Madonna Peter Bo Ngan Robert S Kerbel F Stuart Foster Michelle Letarte

Publish Date: 2013/09/24

Volume: 17, Issue: 1, Pages: 129-146

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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 receptorlike kinase 1 ALK1 HHT2 genes coding for transforming growth factor β TGFβ superfamily receptors Vascular endothelial growth factor VEGF has been implicated in HHT and beneficial effects of antiVEGF treatment were recently reported in HHT patients To investigate the systemic angiogenic phenotype of Endoglin and Alk1 mutant mice and their response to antiVEGF 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 thrombospondin1 TSP1 in Eng +/− versus a rise in angiopoietin2 Ang2 in Alk1 +/− mice AntiVEGF treatment did reduce lung VEGF levels but interestingly led to an increase in peripheral pulmonary MVD and attenuation of RVH it also normalized TSP1 and Ang2 expression Hepatic MVD unaffected in mutant mice was reduced by antiVEGF therapy in heterozygous and wild type mice indicating a liverspecific effect of treatment Contrastenhanced microultrasound demonstrated a reduction in hepatic microvascular perfusion after antiVEGF treatment only in Eng +/− mice Our findings indicate that the mechanisms responsible for the angiogenic imbalance and the response to antiVEGF therapy differ between Eng and Alk1 heterozygous mice and raise the need for systemic monitoring of antiangiogenic therapy effects in HHT patientsWe thank Genentech for kindly providing the G631 antiVEGF 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 MOP6247 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

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